[3.2.0]Bicycloheptanone oxime ethers with valuable therapeutic properties

ABSTRACT

Compounds useful in treating cardiovascular disorders are the carboxylic acids depicted in formulas (1) and (2) ##STR1## as well as their pharmaceutically acceptable, non-toxic salts and esters, wherein: 
     n is an integer from one to four; 
     R 1  is hydroxy; 
     R 2  is hydrogen; or 
     R 1  and R 2  together are an oxo group; 
     R 3  is ##STR2##  wherein A is --CH 2  --CH 2  --; trans--CH═CH--; --C.tbd.C--; and 
     R 4  is linear or branched alkyl of one to twelve carbons, preferably 1-10 carbons, most preferably 3-8 carbons, cycloalkyl of three to eight carbons; phenyl optionally substituted with one or two identical substituents selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, trifluoromethyl, and halo; or phenylloweralkyl optionally substituted with one or two identical substituents selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, trifluoromethyl, and halo.

This application is a continuation-in-part of Ser. No. 397,951, filedJuly 14, 1982, now U.S. Pat. No. 4,423,068.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention concerns novel oxime ether derivatives of certainbicyclo[3.2.0.]heptan-6-ones and pharmaceutically acceptable salts andesters thereof, their use in treating cardiovascular disorders,pharmaceutical compositions containing these compounds, and methods ofpreparing such compounds.

2. Related Disclosures

Bicyclo[3.2.0]hept-2-en-6-one is readily prepared from cyclopentadiene.(J. Org. Chem., 37: 2363, 1972). This and related cycloheptanones arekey intermediates in various prostaglandin syntheses. Bindra and Bindra,Prostaglandin Synthesis, Acad. Press, N.Y. (1977). They are also knownto be used in the manufacture of fragrant compounds (Belgium Pat. No.BE-862-775 to Allen and Hanburys, Ltd.; and Russian Pat. No. SU-639-854to Zelinskii of Org. Chem. Institute, USSR).

Synthetic prostaglandin analogues with a bicyclo [2.2.1]heptane skeletonwhich incorporate an oxime ether moiety in the ω-side chain aredescribed in U.S. Pat. No. 3,872,169 to Bellina of E.I. du Pont deNemours.

Oxyimino-substituted (lR,cis)-cyclopropanecarboxylate andoxyimino-substituted (lR,trans)-cyclopropanecarboxylates are useful aspesticides (U.S. Pat. Nos. 4,211,789 and 4,211,792 to Roman et al ofShell Oil Company, and 4,219,563 to Powel of Shell Oil Company).

Compounds structurally related to those of the present invention arebicyclo[2.2.1]heptanes or heptanones which are substituted at the5-position by a 6-carboxy-hex-2-enyl group and at the 6-position by analdoxime or ketoxime group which is O-substituted by an aliphatic oraromatic hydrocarbon residue or aliphatic hydrocarbon residuesubstituted directly or through an oxygen or sulfur atom by an aromaticresidue. (PCT International Application No. PCT/GB80/00001, PCTInternational Publication No. WO 80/01381).

SUMMARY OF THE PRESENT INVENTION

One aspect of the present invention relates to compounds of the formula(1) and (2) ##STR3## and their pharmaceutically acceptable, non-toxicsalts or esters wherein: n is an integer from one to four;

R₁ is hydroxy;

R₂ is hydrogen; or

R₁ and R₂ together are an oxo group;

R₃ is ##STR4## wherein A is --CH₂ --CH₂ --, trans--CH═CH--, or--C.tbd.C--; and

R₄ is linear or branched alkyl of one to twelve carbons, preferably 1-10carbons, most preferably 3-8 carbons, cycloalkyl of three to eightcarbons, phenyl optionally substituted with one or two identicalsubstituents selected from the group consisting of lower alkyl, loweralkoxy, hydroxy, trifluoromethyl, halo, or phenylloweralkyl optionallysubstituted with one or two identical substituents selected from thegroup consisting of lower alkyl, lower alkoxy, hydroxy, trifluoromethyl,and halo.

Another aspect of this invention is a method of treating cardiovasculardisorders in a mammal by administering a therapeutically effectiveamount of a compound of formula (1) or (2) or their pharmaceuticallyacceptable salts or esters as defined above.

Still another aspect of the invention is a pharmaceutical compositioncontaining a suitable pharmaceutical excipient and a compound of formula(1) or (2) or its pharmaceutically acceptable salts and esters.

Lastly, another aspect of the invention is a process for preparingcompounds of formulas (1) and (2), and their correspondingpharmaceutically acceptable, non-toxic salts and esters, as discussedbelow.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used herein the pharmaceutically acceptable, non-toxic saltderivatives of the compounds of formula (1) and formula (2) arecarboxylic acid salts obtained by reaction of the COOH moiety in formula(1) or (2) with a suitable amine or inorganic base. Specificpreparations are discussed hereinafter.

The pharmaceutically acceptable carboxylic esters corresponding to theacids of formula (1) or (2) are prepared by conventional methods fromthe acid, e.g. by reaction with the appropriate diazoalkane, or anactivated derivative optionally employing a condensing agent such asdicyclohexyl carbodiimide, by reaction of a salt with an appropriateactive alkylating agent, or by ester exchange from an existing ester.Specific preparations are described in the procedures and examplesbelow.

"Oxo group" as used herein means an oxygen attached to a carbon atom bya double bond.

The term "alkyl" refers to and includes saturated branched and straightchain hydrocarbon radicals containing the number of carbons indicated.Typical alkyl groups include methyl, ethyl, propyl, isopropyl, butyl,tertiary butyl, neopentyl, isopentyl, hexyl, octyl, nonyl, isodecyl,6-methyldecyl.

"Cycloalkyl" as used herein means a saturated monocyclic hydrocarbonradical containing 3-8 carbon atoms, such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

The term, "lower alkyl" refers to a branched or unbranched saturatedhydrocarbon chain of 1-4 carbons, such as, for example, methyl, ethyl,n-propyl, i-butyl and the like.

The term "alkoxy" refers to the radical -0-alkyl wherein "alkyl" is asdefined above. This includes radicals such as methoxy, ethoxy,2-propoxy, butoxy, 3-pentoxy and the like.

"Lower alkoxy" means the group -OR wherein R is lower alkyl as hereindefined.

"Halo" as used herein denotes fluorine, chlorine, bromine, or iodine.

"Substituted phenyl" as used herein encompasses all possible isomericphenyl radicals mono- or disubstituted with a substituent selected fromthe group consisting of lower alkyl, lower alkoxy, hydroxy,trifluoromethyl and halo, with the proviso that in the disubstitutedcase both substituents must be the same.

"Optional" or "optionally" means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. For example, "optionally substituted phenyl" means that thephenyl may or may not be substituted and that the description includesboth unsubstituted phenyl and phenyl wherein there is substitution.

"Inhibitor" as used herein means a chemical entity which has thecapability to restrain, stop or retard a physiologic, chemical orenzymatic action. To be an effective inhibitor, the chemical entity mustbe effective in low concentration. The effectiveness of the inhibitor isdetermined by establishing the minimum concentration required to producea specified degree of inhibition of the target chemical or otherreaction. The lower the effective concentration, the stronger theinhibitor.

"Inhibitors of platelet aggregation" as used herein are chemicalentities which are effective in preventing a normally caused (bybleeding or damage of endothelium of a blood vessel) or artificiallycaused (by appropriate inducer) platelet aggregation. Inhibitory effectof the claimed compounds is expressed as inhibitory concentration IC₅₀and as the potency of an inhibitor.

"Inhibitory concentration (IC₅₀)" as used herein is the concentration ofthe inhibitor which is necessary to effect a 50% reduction of theaggregatory response to a standard dose of a stimulant of plateletaggregation inducer.

"Potency of inhibitor" as used herein is expressed relative to thepotent natural inhibitor PGE₁. Thus for a test compound A, ##EQU1##

The designation "ω" as used hereinafter to denote the position of asubstituent in a straight chain carboxylic acid, identifies the mostremote atom, i.e. the terminus of the chain. Thus ω-aminocaproic acid=6-aminocaproic acid, while ω-bromo dodecanoic acid =12-bromododecanoicacid.

The numbering system for the bicyclo [3.2.0] heptane system is shown inthe scheme illustration and is used in naming the intermediates andproduct compounds of the invention. ##STR5##

The prefixes exo- and endo- are used in their conventional fashion todenote the stereochemistry (cis- and trans-, respectively) ofsubstituents with reference to the ring junction hydrogens (H-1, H-5).When a particular stereochemistry is implied in the structural drawings,exo- bonds are shown by solid lines, while broken lines indicateendo-substituents. Thus in the scheme illustration above,

R¹ =3-endo

R² =3-exo

R³ =2-exo

and the stereochemical designations α and β are applied to a hydroxylsubstituent in R₃ and these terms designate a broken line bond and asolid line bond to the hydroxyl respectively. Classical nomenclature isused to name a compound having a triple bond as alkynyl; a double bondas alkenyl; a single bond as alkyl; and two bonds emanating from thesame atom as -ylidene. Exemplary names are given in the "PreferredEmbodiments" section of this application.

PREFERRED EMBODIMENTS OF THE INVENTION

One subclass of compounds of the invention is represented by formula (1)wherein n is 1, 2, or 3. ##STR6##

One preferred subgroup includes the compounds of formula (1) wherein nis 3 or 1; R₁ is hydroxy; R₂ is hydrogen, R₃ is ##STR7## R₄ is alkyl of1 to 12 carbons, preferably 1-10 carbons, most preferably 3-8 carbons;and the pharmaceutically acceptable, non-toxic salts and esters thereof.Compounds representative of this subgroup are

N-[3-endo-hydroxy-2-exo-(3-hydroxy-alk-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid and

N-[3-endo-hydroxy-2-exo-(3-hydroxy-alk-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid.

A more preferred subclass of compounds are those represented by formula(2) wherein n is 1, 2 or 3. ##STR8## and a most particularly preferredsubgroup of compounds are those represented by formula (2) wherein n is1 or 2; R₁ is hydroxy; R₂ is hydrogen; R₃ is ##STR9## with thosecompounds wherein R₄ is alkyl of 1-10 carbons, in particular, alkyl of3-8 carbons such as n-pentyl, cyclopentyl or cyclohexyl being of thehighest preference, and their pharmaceutically acceptable, non-toxicsalts and esters. This class encompasses but is not limited to thefollowing compounds:

N-[2-endo-hydroxy-3-exo-(3-hydroxy-but-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-pent-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-hex-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-hept-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-non-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-dec-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-undec-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-dodec-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclopentylprop-1-ynyl)-bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclohexylprop- 0-ynyl)-bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionic acid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-phenylprop-1ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid; and

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-(2-trifluoro-methyl)phenylprop-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid.

N-[2-endo-hydroxy-3-exo-(3-hydroxy-but-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-pent-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-hex-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-hept-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-non-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-dec-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-undec-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-dodec-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclopentylprop-1-ynyl)-bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclohexylprop-1-ynyl)-bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-phenylprop-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid; and

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-(2-trifluoromethyl)phenylprop-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid.

N-[2-endo-hydroxy-3-exo-(3-hydroxy-but-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-pent-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-hex-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-hept-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-oct-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-non-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-dec-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-undec-1-transenyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionic

N-[2-endo-hydroxy-3-exo-(3-hydroxy-dodec-1-transenyl)-bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionic

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclopentylprop-1-trans-enyl)-bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclohexylprop-1-trans-enyl)-bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-phenylprop-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionic acid; and

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-(2-trifluoromethyl)phenylprop-1-trans-enyl)bicyclo[3.2.0]hept-6ylidene]-3-aminooxypropionicacid.

N-[2-endo-hydroxy-3-exo-(3-hydroxy-but-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-pent-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-hex-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-hept-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-oct-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-non-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-dec-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-undec-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-dodec-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclopentylprop-1-trans-enyl)-bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclohexylprop-1-trans-enyl)-bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-phenylprop-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid; and

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-(2-trifluoromethyl)phenylprop-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid.

PREPARATION PROCEDURES

Compounds wherein R₁ is hydroxy and R₂ is hydrogen are preparedaccording to the Reaction Scheme 1. ##STR10##

In the detailed description, the Roman numerals in parentheses show thesteps in the reaction scheme.

Synthesis of compounds (I) through (VI) is described in detail in U.S.Pat. No. 4,272,629 to Roberts.

The synthesis of the compounds of formula (1) and (2) begins withreaction of cyclopentadiene (I) with dichloroacetyl chloride forming7,7-dichlorobicyclo[3.2.0]hept-2-en-6-one (II) which, when reacted withzinc dust, results in formation of bicyclo[3.2.0]hept-2-en-6-one (III).J. Org. Chem., 37:2363 (1972).

Bicyclo[3.2.0]hept-2-en-6-one is reacted with1,3-dibromo-5,5-dimethylhydantoin in the presence of aqueous acid toform the bromohydrin (IV) which, in turn, is reacted with ethyleneglycol to give the acetal (V). The acetal is subsequently reacted withsodium hydroxide in methanol to form the epoxy acetal (VI). Cave et al,J.C.S. Perkin I.:2955 (1979).

The bicyclic epoxy acetal (VI) can be reacted with a variety ofmetal-organic reagents of general structure M--R₃ ' to give theregioisomeric products of epoxide cleavage, VIIA' and VIIB', where##STR11## in which A and R₄ are as previously defined and Pt is aprotecting group for the side chain hydroxyl function. Suitableprotecting groups include, but are not limited to, silyl ethers,tertiary alkyl ethers, e.g. tert-butyl, (optionally substituted)triphenylmethyl ethers, acetals such as tetrahydropyranyl ethers, andthe like. Usually trialkyl silyl ethers are preferred, and particularlypreferred are the tert-butyldimethylsilyl derivatives. These ethers areprepared from the corresponding carbinols by standard procedures wellknown to those skilled in the art; the tert-butyldimethylsilyl ethers inparticular enjoy obiquitous use in prostaglandin chemistry and can beconveniently prepared by reaction of the appropriate carbinol withtert-butyldimethylsilyl chloride in N,N-dimethylformamide solution inthe presence of imidazole, which functions in the dual capacities ofspecific catalyst for the silylation and as base, to neutralize thehydrochloric acid which constitutes the other reaction product.Representative procedures for preparing the silyloxy and other protectedcarbinols are given in the references for preparation of the varioustypes of organometallic reagents that can be employed to effectalkylative opening of the epoxy acetal (VI).

Organometallic reagents of the alkynyl type are prepared from thecorresponding 1-alkyn-3-ols, which in turn can be readily obtained byreaction of an acetylenic Grignard reagent, i.e. ethynyl magnesiumhalide, or lithium acetylide, with aldehydes ##STR12## furnishingethynyl carbinols ##STR13## Protection of the hydroxyl group gives thecorresponding ethers ##STR14## Conversion to an organometallic reagentcan now be effected, usually by exchange reaction with a stoichiometricquantity of a more reactive organometallic, e.g. an alkyl Grignardreagent RMgCl to give the acetylene Grignard reagent ##STR15## or withan alkyl lithium reagent R Li to furnish the corresponding lithiumacetylide. Reaction of the latter with, e.g., dimethyl aluminum chloridefurnishes an alane ##STR16## This species may be further reacted with analkyl lithium reagent, e.g. CH₃ Li, to give yet another organometallicreagent useful for effecting alkylative epoxide opening, namely thealanate ##STR17## Detailed descriptions of alane preparations and theirreaction with cyclopentene-derived epoxides are given in TetrahedronLett.;3899 (1973); of alanate preparations and acetylenic Grignards(U.S. Pat. 4,197,295) and of lithium alkynyl species, inter alia byStork et al, J. Amer. Chem. Soc., 96, 7114 (1974); ibid., 97, 4745(1975).

The novel products of our invention in which A is a trans-olefiniclinkage can be prepared according to the Scheme from the acetyleniccarbinol products of epoxide opening ##STR18## by reduction, e.g. withlithium aluminum hydride, to furnish the trans-olefinic carbinols (see1975 Stork and Isobe ref. above for an example utilizing this LAHreduction in a total synthesis of prostaglandins). A convenient andgeneral method for preparation of the olefinic species involvespreparation of organocopper reagents containing the desired olefinicmoiety. These can be prepared easily from the vinyl lithium derivatives,which in turn are obtained by reaction of the appropriate trans-vinylhalide, preferably iodide, with an alkyl lithium reagent or with lithiummetal. Detailed descriptions of the preparation of various olefinicorganocuprate reagents representing both hetero- and homocupratestructure types, and their reactions with compound VI and relatedbicyclic epoxy acetals are given in U.S. Pat. No. 4,272,629 to Robertsand references therein.

The products of our invention in which the chain is fully saturated(A=--CH₂ CH₂ --) may be prepared by direct introduction of the saturatedside chain via the corresponding organometallic reagent ##STR19## whichcan be prepared by standard methods from the corresponding halides##STR20## by reaction in an ethereal solvent, preferablytetrahydrofuran, with a metal, e.g. Mg or Li, or by exchange with a morereactive organometallic reagent, e.g. an aryl lithium derivative. Thesaturated side chain species may also, and preferably, be prepared bycatalytic hydrogenation, using noble metal catalysts (palladium oncarbon, rhodium on carbon, rhodium on alumina, platinum), of either thealkynyl or alkenyl side chain products. These hydrogenations proceedwith facility by stirring a solution of the substrate at ambienttemperature and low hydrogen pressures (1-4 atm.) in the presence of1-10% (w/w) of a catalyst. A variety of solvents may be employed,alcohols such as methanol and ethanol being particularly useful.Reaction times vary from less than 1 to 24 hours depending on thesolvent, the nature and quantity of the catalyst employed, and thestructure of the substrate being reduced, but can be convenientlymonitored since when the stoichiometric quantity of hydrogen has beentaken up (1 mole equiv. for alkene, 2 mole equiv. for alkyne startingmaterials) the reduction to saturated alkylene side chain is essentiallycomplete. Catalyst is removed from the hydrogenation mixture byfiltration, preferably through a pad of diatomaceous earth. Evaporationof the filtrates under reduced pressure then furnishes a residue of thedesired 2- or 3-exo-alkylidene bicycloheptan-6-one derivative, typicallyrequiring no further purification. When desired, final purification isreadily effected by preparative layer or column chromatography on silicagel. When the ω-chain being hydrogenated terminates in a phenyl ring, apalladium/carbon catalyst is preferred, and when said phenyl ringcarries 1-2 halogen substituents, in particular Br or I, reduction ofthe C--C multiple bond(s) may be accompanied by some degree of reductivedehalogenation. Such dehalogenated by products can usually be separatedby chromatography but, if this proves tedious, those particularfunctionalized chains can be introduced directly in their saturated form(see above) by reaction of the corresponding terminal Grignard ororganolithium reagents with epoxyacetal VI.

An organometallic reagent may react with epoxyacetal VI at eitherterminus of the oxirane ring to furnish two regioisomeric alcohols, andin fact both regioisomers are obtained. For example, reaction of VI with3-(tert-butyldimethylsilyloxy)oct-1-ynyl dimethyl alane furnishes theregioisomeric alkynyl carbinols

VIIA--3-endo-hydroxy-2-exo-(3-hydroxyoct-1-ynyl)spiro[bicyclo-[3.2.0]heptan-6,2'-[1.3]dioxolan];and

VIIB--2-endo-hydroxy-3-exo-(3-hydroxyoct-1-ynyl)spiro[bicyclo-[3.2.0]heptan-6,2'-[1,3]dioxolan].

The two isomers are separated chromatographically, and the alkynolacetals VIIA and VIIB are each reacted with sulfuric acid to effectacetal hydrolysis furnishing3-endo-hydroxy-2-exo-(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-one(VIIIA) and2-endo-hydroxy-3-exo-(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-one(VIIIB), respectively. (J. Chem. Soc., Perkin I, 852, (1980)).

For the preparation of 3-aminooxypropionic acid the methods described inJ. Am. Chem. Soc., 77, page 2345 (1955), in U.S. Pat. No. 2,762,815, andin Zhur. Obshchei Khim. 31, 1992 (1961) were modified as follows.Acetone oxime in dioxane is reacted with sodium methoxide and methylacrylate, acidified and distilled to provide the acetone oxime of3-aminoxypropionic acid, which is subsequently hydrolyzed to form3-aminooxypropionic acid hydrochloric acid salt.

In carrying out this reaction, as set forth above, typically acetoneoxime dissolved in dioxane is added to sodium methoxide and the mixtureis stirred from 15 minutes to about 2 hours, preferably 30 minutes, thencooled to 0° C. with an ice bath for about 1 hour or until 0° C.temperature of the mixture is achieved. After methyl acrylate is added,the resulting mixture is warmed to room temperature and stirred forabout 2 to 5 hours, preferably 3 hours. After acidifying and purifyingby distillation, the oxime adduct is heated in the presence of an acidcatalyst, preferably 5N hydrochloric acid, at 40° to about 80° C.,preferably to 60° C., until the reaction is complete.

The synthesis of 4-aminooxybutyric acid and 5-aminooxyvaleric acid aredescribed in Tetrahedron, 23, 4441 (1967). Benzophenone oxime inN-methylpyrrolidone is reacted first with sodium then withγ-butyrolactone to provide N-diphenylmethylidene-4-aminooxybutyric acidwhich is subsequently hydrolyzed to form 4-aminooxybutyric acid.5-aminooxyvaleric acid hydrochloric acid salt is prepared similarly bysubstituting γ-butyrolactone with σ-valerolactone. Aminooxyacetic acidis available as the hemihydrochloride from a commercial source.

Bicycloheptanone alkynol formula (VIIIB) is reacted with ω-aminooxycarboxylic acids having 2-5 carbon atom chain length to result information of the correspondingN-[2-endo-hydroxy-3-exo-(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-ω-aminooxyalkanoic acids. Bicycloheptanone alkynol formula (VIIIA) is reacted withω-aminoxy acids of 2-5 carbon atoms to form the isomericN-[3-endo-hydroxy-2-exo-(3-hydroxy-oct-1-ynyl)bicyclo-[3.2.0]hept-6-ylidene]-ω-aminooxy alkanoic acids.

In carrying out this reaction, as set forth supra, typically oneequivalent of bicycloheptanone and 2 equivalents of sodium acetate aredissolved in alcohol, preferably methanol and added to a salt,preferably hydrochloride, of the aminooxy acid also dissolved in stirredat ambient temperature for 0.5 to 7 hours until the reaction isdetermined to be complete. After removing the alcohol, the residue isextracted several times with an organic solvent such as ethyl acetate,methylene chloride and the like. Combined extracts are washed withaqueous salt solution, dried, e.g. over MgSO₄, and evaporated underreduced pressure. The residue is purified by recrystallization from asuitable organic solvent or mixture of solvents, e.g. ethylacetate-heptane, to furnish the pure oximino acid. ##STR21##

The novel compounds of our invention wherein the groups R₁ and R₂ takentogether denote a carbonyl group are readily prepared according to theReaction Scheme by judicious selection of a protecting group for the3-hydroxyl function in the organometallic reagent used to open epoxyacetal VI such that it will be sufficiently stable to remain intactduring hydrolytic cleavage of the cyclic acetal, i.e. VIIA' IXA or VIIB'IXB in the reaction flow sheet.

The resulting ketone is then reacted with the appropriateω-aminoxycarboxylic acid (IXA XA) or (IXB XB) as described above, andthe free ring hydroxyl group in the product is then oxidized, e.g., witha chromium trioxide reagent such as that of Jones or Collins, or with adimethyl sulfoxide reagent (the Moffatt reagent, or variousmodifications thereof), or a dimethyl sulfonium species such as thatdescribed by Corey and Kim in J. Am. Chem. Soc., 94:7586 (1972) tofurnish the corresponding ring ketone XIA or XIB, respectively.Hydrolysis of the remaining protecting group in the ω-side chain thenfurnishes the compounds of our invention of formula (1) or (2) whereinR₁ and R₂ taken together are a carbonyl group.

A useful protecting group for this sequence of reactions is thetert-butyldimethylsilyloxy group. Employment of this group in themetallorganic reagent used to open epoxide (VI) furnishes a silyloxyhydroxyacetals VIIA' and VIIB'. Selective hydrolysis of the ketalfunction can now be effected by exchange ketalization. Thus, when asolution of the protected ketal VII' in a ketonic solvent, preferablyacetone, is allowed to stand at temperatures between -30 and 20° C. inthe presence of a catalytic amount of a mineral acid or strong organicacid, the ketal function is transferred to the solvent to give as thepredominant reaction product the silyloxy-hydroxyketone (IX) which isisolated, after neutralization of the reaction mixture, by conventionalmeans. The exchange reaction is conveniently carried out at about 0° C.,and p-toluenesulfonic acid is a preferred acid catalyst. Progress of theketal exchange is conveniently monitored by T.L.C.

Preparation of the oxime products results in an equilibrium mixture ofsyn- and anti- oxime isomers, which can be separated by chromatographyover silica gel. While only one geoisomer may be depicted in theaccompanying structural diagrams, this invention encompasses both syn-and anti- oxime geoisomers and mixtures thereof in any proportions.

The structures depicted herein, including the novel compounds of ourinvention, have multiple chiral centers and are optically active. Whilefor illustrative purposes only one optical isomer is depicted, ourinvention encompasses all optical isomers and mixtures thereof, saidmixtures including racemates and diastereomeric mixtures in allproportions. If the product compounds of our invention are prepared fromoptically inactive starting materials and without employment of chiralreagents, the products will be obtained as (optically inactive) racemicmixtures. Enantiomerically pure materials can be obtained, e.g., byresolution of the final product acids via their salts with opticallyactive amines according to methods well-known in organic chemistry andspecifically in the chemistry of prostaglandins.

An alternative route to optically active products proceeds via chiralintermediates. An efficient synthesis of both bicyclo[3.2.0]hept-2-en-6-one enantiomers, involving enantioselective reductionby fermenting baker's yeast of the racemic bicycloheptenone, has beendescribed (Davis et al., J. Chem. Soc., Chem. Commun., 1317, 1981). Bothenantiomeric ω-side chain alcohols, e.g. (R)- and (S)-1-octyn-3-ols, arealso readily available (J. Fried et al., Ann. N.Y. Acad. Sci., 180, 39,(1971)). Thus, condensation of an organometallic derived from opticallyactive side chain alcohol with one optical isomer of bicycloheptanoneexpoxy acetal (VI) will lead to a single optical isomer product (VII)and eventually to the corresponding pure optical isomer products of ourinvention. Reaction of optically active side chain with racemicbicycloheptanone acetal epoxide, or racemic side chain with opticallyactive bicycloheptanone acetal epoxide, will lead to mixtures ofdiastereomeric products which can be employed per se or can be separatede.g. by chromatographic methods to furnish enantiomerically purematerials.

This method is shown in Reaction Scheme 3 wherein a diastereisomericmixture of3-exo-(3S-t-butyldimethylsilyloxyalk-1-ynyl)spiro[bicyclo(3.2.0)heptan-6,2'-(1,3-dioxolan]-2-endo-ols(VIIB' in Reaction Scheme 1) is converted through reaction with dicobaltoctacarbonyl in diethyl ether into their dicobalthexacarbonyl complexes(αS-XIIB and βS-XIIB), which are separated chromatographically. Theisolated complexes are converted with ceric ammonium nitrate back intotheir parent enantiomeric3-exo-(3βS-t-butyldimethylsilyloxyalk-1-ynyl)spiro[bicyclo(3.2.0)heptan-6,2'-(1,3)dioxolan]-2-endo-olsand3-exo-(3βS-t-butyldimethylsilyloxyalk-1-ynyl)spiro[bicyclo(3.2.0)heptan-6,2'-(1,3)chromatographically.The isolated complexes are converted with ceric ammonium nitrate backinto their parent enantiomeric3-exo-(3βS-t-butyldimethylsilyloxyalk-1-ynyl)spiro[bicyclo(3.2.0)heptan-6,2'-(1,3)dioxolan]-2-endo-olsand3-exo-(3αS-t-butyldimethylsilyloxyalk-1-ynyl)spiro[bicyclo(3.2.0)heptan-6,2'-(1,3)dioxolan]-2-endo-ols.These are converted into the corresponding2-endo-hydroxy-3-exo-(3βS-hydroxyalk-1-ynyl)bicyclo[3.2.0]heptan-6-one(βS-VIIIB) and2-endo-hydroxy-3-exo-(3αS-hydroxyalk-1-ynyl)bicyclo[3.2.0]heptan-6-one(αS-VIIIB) through hydrolysis with dilute aqueous acid. These compoundsare converted into theirN-[2-endo-hydroxy-3-exo-(3βS-hydroxyalk-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]aminooxyalkanoicacid (βS-Formula 2) andN-[2-endo-hydroxy-3-exo-(3αS-hydroxyalk-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]aminooxyalkanoicacid (αS-Formula 2). ##STR22##

As used herein the pharmaceutically acceptable non-toxic saltderivatives of the compounds of formula (1) and formula (2) are preparedby treating the free acids with an appropriate amount ofpharmaceutically acceptable base. Representative pharmaceuticallyacceptable bases are sodium hydroxide, potassium hydroxide, lithiumhydroxide, ammonium hydroxide, calcium hydroxide, magnesium hydroxide,ferrous hydroxide, zinc hydroxide, copper hydroxide, manganoushydroxide, aluminum hydroxide, ferric hydroxide, manganic hydroxide,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, lysine, arginine, histidine, procaine, choline,betaine, ethylenediamine, glucosamine, methylglucamine, theobromine,purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins andthe like. The reaction is conducted in water, alone or in combinationwith an inert, water-miscible organic solvent, at a temperature of fromabout 0° C. to about 100° C., preferably at room temperature. Typicalinert, water-miscible organic solvents include methanol, ethanol,isopropanol, butanol, acetone, dioxane or tetrahydrofuran. The molarratio of compounds of formula (1) or (2) to base used are chosen toprovide the ratio desired for any particular salt. For preparing, forexample, divalent cation salts such as the calcium or magnesium saltsthe free acid starting material of formula (1) or (2) is treated with atleast one-half molar equivalent of pharmaceutically acceptable base toyield a neutral salt. Similarly, for the trivalent cation aluminumsalts, at least one-third molar equivalent of the aluminum base isemployed if a neutral salt product is desired.

The novel free carboxylic acids (1) and (2) of our invention can bereliberated from their respective salts by treating said salts with atleast stoichiometric quantities of a strong acid, preferably aninorganic acid, e.g., hydrochloric acid, sulfuric acid, and the like, attemperatures ranging from about 0° C. to about 50° C., preferably atroom temperature.

The pharmaceutically acceptable non-toxic esters of the novel acids (1)and (2) of our invention can be prepared, e.g. by esterifying thecorresponding free acids with a solution of the appropriate diazoalkanein a suitable inert solvent such as diethyl ether. An alternative andgeneral method for producing the esterified acids of our inventioncomprises reaction of a benzene solution of the carboxylic acid with analkyl halide in the presence of the organic base diazabicycloundecane(DBU) at temperatures from about 20° C.-80° C., and for about 1-12hours. These conditions are particularly useful for esterifying acidscontaining labile functionality in the molecule, such as theprostaglandins and their synthetic analogues, since they avoid the useof acid catalysts and in fact involve no harsh reagents. (N. Ono et al,Bull. Chem. Soc. Japan, 51, 2401-2404 (1978)).

Typical esters are those esters derived from methyl alcohol, ethylalcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, 2-butylalcohol, 2-pentyl alcohol, isopentyl alcohol, 2-hexyl alcohol, and thelike.

Alternatively, the alkyl esters can be prepared by transesterification,catalyzed by the corresponding alkoxide according to methods known inthe art. It is preferred in preparing the esters via transesterificationto go from a lower ester to a higher ester, e.g., from the methyl esterto the isoamyl ester. However, by using a substantial excess of a loweralcohol, a higher ester can be transesterified to a lower ester; thus,for example, by using a substantial excess of ethanol, the hexyl esteris converted by transesterification to the ethyl ester.

Salts of the compounds of formula (1) and (2) may be interchanged bytaking advantage of differential solubilities of the salts volatilitiesor activities of the acids, or by treating with the appropriately loadedion exchange resin. For example, the interchange is effected by thereaction of a salt of the compounds of formula (1) or (2) with a slightstoichiometric excess of an acid of a lower pKa than the acid componentof the starting salt. This conversion is carried out at a temperaturebetween about 0° C. and the boiling point of the solvent being used asthe medium for the procedure.

UTILITY AND ADMINISTRATION

The compounds of the present invention are synthetic prostaglandinanalogs and display the spectrum of biological activities associatedwith prostacyclin (PGI₂). They are useful for the treatment ofcardiovascular disorders; in particular they are potent plateletaggregation inhibitors. Accordingly, these compounds are useful intreating cardiovascular disorders with thrombotic complications. Theyalso are useful as vasodilatory, antisecretory and antihypertensiveagents.

Because these compounds are synthetic prostaglandin analogs andspecifically analogs of prostacyclin PGI₂ they display the spectrum ofactivities associated with prostaglandin. However, in contrast toprostacyclin, whose therapeutic potential is severely compromised by itsextreme chemical instability, the compounds of our invention retain highbiological activity while displaying much greater chemical stability, acombination of attributes identifying them as promising agents forprophylactic and/or therapeutic use particularly in the treatment ofcardiovascular dysfunction and disease.

Administration of the active compounds in the pharmaceutical compositiondescribed hereinafter can be via any of the accepted modes ofadministration for agents which affect the cardiovascular system. Thesemethods include oral, parenteral and otherwise systemic administration.Depending on the intended mode, the composition may be in the form ofsolid, semi-solid or liquid dosage forms, such as, for example, tablets,suppositories, pills, capsules, powders, liquids, suspension, or thelike, preferably in unit dosage forms suitable for single administrationof precise dosages. The composition will include a conventionalpharmaceutical carrier or excipient and an active compound of formula(1) or (2) and/or the pharmaceutically acceptable salts thereof and, inaddition, may include other medicinal agents, pharmaceutical agents,carriers, adjuvants, etc.

The present invention further relates to a method for treating symptomsassociated with cardiovascular disorders in mammals, which methodcomprises administering to a subject in need thereof an effective amountof a compound selected from those represented by formulas (1) and (2) ortheir pharmaceutically acceptable non-toxic salts or esters, or apharmaceutical composition incorporating such compound(s) as an activeingredient.

The present invention still further relates to pharmaceuticalcompositions useful for treating cardiovascular disorders. Thesecompositions comprise an effective amount of a compound selected fromthose represented by formulas (1) and (2) or their pharmaceuticallyacceptable non-toxic salts or esters in acceptable, non-toxic carrier.

The amount of active compound administered will of course, be dependenton the subject being treated, the severity of the affliction, the mannerof administration and the judgment of the prescribing physician.However, an effective dosage will be in the range of 0.001-15 mg/kg/day,preferably 0.01-3 mg/kg/day. For an average 70 kg human, this wouldamount to 0.07-1000 mg per day, or preferably 0.7-210 mg/day.

The novel compounds of this invention may be formulated with suitablepharmaceutical vehicles known in the art to form particularly effectivecardiovascular composition. Generally, an effective amount of activeingredient is about 0.001% w to about 10% w of the total formulatedcomposition. The rest of the formulated composition will be about 90% wto about 99.999% w of a suitable excipient.

For solid compositions, conventional non-toxic solid carriers include,for example, pharmaceutical grades of mannitol, lactose, starch,magnesium stearate, sodium saccharin, talcum, cellulose, glucose,sucrose, magnesium carbonate, and the like may be used. The activecompound as defined above may be formulated as suppositories using, forexample, polyalkylene glycols, for example, propylene glycol, as thecarrier. Liquid pharmaceutically administerable compositions can, forexample, be prepared by dissolving, dispersing, etc. an active compoundas defined above and optional pharmaceutical adjuvants in a carrier,such as, for example, water, saline, aqueous dextrose, glycerol,ethanol, and the like, to thereby form a solution or suspension. Ifdesired, the pharmaceutical composition to be administered may alsocontain minor amounts of nontoxic auxiliary substances such as wettingor emulsifying agents, pH buffering agents and the like, for example,sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate,triethanolamine oleate, etc. Actual methods of preparing such dosageforms are known, or will be apparent, to those skilled in this art; forexample, see Remington's Pharmaceutical Sciences, Mack PublishingCompany, Easton, Pa., 15th Edition, 1975. The composition or formulationto be administered will, in any event, contain a quantity of the activecompound(s) in an amount effective to alleviate the symptoms of thesubject being treated.

Parenteral administration is generally characterized by injection,either subcutaneously, intramuscularly or intravenously. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions, solid forms suitable for solution or suspension in liquidprior to injection, or as emulsions. Suitable excipients are, forexample, water, saline, dextrose, glycerol, ethanol or the like. Inaddition, if desired, the pharmaceutical compositions to be administeredmay also contain minor amounts of non-toxic auxiliary substances such aswetting or emulsifying agents, pH buffering agents and the like, such asfor example, sodium acetate, sorbitan monolaurate, triethanolamineoleate, etc.

A more recently devised approach for parenteral administration employsthe implantation of a slow-release or sustained-release system, suchthat a constant level of dosage is maintained. See, e.g., U.S. Pat. No.3,710,795.

For systemic administration via suppository, traditional binders andcarriers include, e.g. polyalkylene glycols or triglycerides. Suchsuppositories may be formed from mixtures containing active ingredientin the range of 0.5%-10%; preferably 1-2%.

The following Preparations and Examples serve to illustrate theinvention and make the invention enabling. They should not be construedas narrowing it or limiting its scope in any way.

In the Preparations and Examples, the use of Roman numerals refers tothe reaction steps on Reaction Scheme.

PREPARATION PROCEDURES FOR COMPOUNDS OF THE FORMULA VIII Preparation 1Preparation of 7,7-dichlorobicyclo(3.2.0)hept-2-en-6-one

Over a period of 1.5 hr 21.7 g of dry triethylamine in 200 ml of hexanewas added to a vigorously stirred solution mixture of 27.2 g of freshlydistilled cyclopentadiene (I), 30.5 g of dichloroacetyl chloride, and200 ml of hexane (dried over molecular sieves). After stirring for 15hours under an atmosphere of nitrogen, the reaction mixture was filteredand the filter cake was washed with hexane. The solvent was removedunder vacuum, yielding a 35.2 g of liquid, which, when redistilled undervacuum, afforded 30 g of 7,7-dichlorobicyclo(3.2.0)hept-2-en-6-one (II).

Preparation of bicyclo(3.2.0)hept-2-en-6-one

5.00 g (0.028 mol) of 7,7-dichlorobicyclo(3.2.0) hep-2-en-6-one in 5 mlof glacial acetic acid was added dropwise to a vigorously stirredsuspension of 11.0 g of zinc dust in 15 ml of glacial acetic acid atroom temperature. After addition was completed, the temperature wasraised to and maintained at 70° C. for 40 minutes. A thin layerchromatography (TLC) analysis performed at that time indicated noremaining starting material. The reaction mixture was then cooled andtreated with ether. Zinc residue was filtered. The ethereal layer waswashed with saturated solution of Na₂ CO₃ to remove remaining aceticacid and subsequently dried over the magnesium sulfate. The solvent wasthen evaporated and the product, bicyclo(3.2.0)hept-2-en-6-one (III),was isolated by distillation. The total yield of the product was 2.99 g(95%). The homogeneity of the product was determined by TLC.

Preparation 2 Conversion of bicyclo(3.2.0)hept-2-en-6-one into theepoxyacetal of Formula (VI)

To 1 g of bicycloheptenone (III) dissolved in the mixture of 20 ml ofacetone and 5 ml of water, 1.5 g of 1,3-dibromo-5,5-dimethyl-hydantoinwas added in portions under constant stirring. After 16 hours at roomtemperature the solvent was evaporated under reduced pressure. Theresidue was dissolved in 10 ml of water and extracted several times withdichloromethane. Obtained organic extracts were washed with brine, driedover magnesium sulfate and evaporated. A residuum in the form of ayellow oil was then separated by silica-gel column chromatography withsolvent mixture of 20% ethyl acetate in light petroleum to obtain2-bromo-3-hydroxybicyclo[3.2.0]heptan-6-one (IV) (U.S. Pat. No.4,272,629).

A mixture of 17.5 g of this bromohydrin, 8.0 g of ethylene glycol and0.17 g of toluene-p-sulfonic acid monohydrate was heated under reflux in175 ml of benzene under nitrogen. Water was removed using a Dean-Starktrap, and after 6 hours the solution was cooled and washed with an 8%(weight/volume) solution of sodium bicarbonate-water and water. Thedried (over MgSO₄) solution was decolorized with charcoal and thesolvent was evaporated to give a residue of bromohydrin-acetalrepresented by formula (V).

10.6 g of the bromohydrin-acetal was dissolved in 25 ml of sodiumhydroxide in 75 ml of methanol. The whole solution was incubated for 20hours at 20° C., then 200 ml of water was added prior to extraction with30 ml of dichloromethane. Extraction was repeated four times, extractswere combined, washed with water, dried and evaporated. Evaporated oilyresiduum was distilled and the product of distillation slowlycrystallized into the epoxyacetal represented by Formula (VI).

Preparation 3 Preparation of 3-OH Alkynes and 3-OH Alkenes 3.A.Preparation of 1-yn-3-ols

A rapid stream of acetylene was passed through a solution of 2M methylmagnesium bromide (100 ml) in THF until no more methane evolution wasobserved. 10 g of hexanal was added at 0° C., stirred for 1/2 h and asaturated solution of NH₄ Cl was added. The organic product was isolatedby extraction with ether. The ether solution was washed with water,brine, dried over MgSO₄ and evaporated to give a liquid which waspurified by distillation.

3.B. Preparation of 1-Iodo-trans-1-octen-3-ol Step 1

To 400 ml of distilled methylene chloride 44 g of aluminum trichlorideand 40 g of hexanoyl chloride is added. The reaction mixture ismaintained at 15° C. with an external cooling bath. Over the period of1/4 hours 27 ml of dry acetylene is delivered. The temperature is keptat about 15° C. The progress of the reaction is followed by I.R(disappearance of acid chloride carbonyl). Upon completion of thereaction, the reaction solution is transferred to 800 ml of water at 5°C. with vigorous stirring. 500 ml of methylene chloride is added andmethylene chloride layer is separated. The aqueous phase is extractedwith 100 ml of methylene chloride. Combined methylene chloride extractsare washed 3 times with 100 ml of water, dried over anhydrous sodiumsulphate, and the solvent evaporated in vacuo. The crude oil is purifiedby distillation under high vacuum.

Step 2

30 g of sodium iodide is stirred with 80 ml of distilled acetone. 20.4 gof crude oil (obtained during Step 1) in acetone is added. The resultingmixture is kept under constant reflux for approximately 8 hours. Themixture is filtered through a Buchner funnel, the filter cake washedwith 20 ml of acetone, and the combined filtrates concentrated underreduced pressure at a temperature below 40° C., ca. 50 ml of benzenebeing added to displace all the acetone. The aqueous phase is extractedtwice with 20 ml of benzene. The benzene layer is washed to neutralitywith water, then dried over anhydrous sodium sulphate. The solvent isremoved in vacuo to give approximately 30 g of oil. The oil is dissolvedin 50 ml of diethyl ether/hexane (25:75, v:v) and filtered through 20 gof silica gel. The resulting oil is distilled under high vacuum to give26.8 g of product.

Step 3

32 g of iodoketone in 50 ml of benzene is under nitrogen to 0°-5° C. 28ml of 65% Vitrid™ is added dropwise with constant stirring. The reactionis followed by TLC employing a solvent system ether/hexane (25:75, v:v).9.3 ml of sulfuric acid in 50 ml of water is added dropwise underconstant stirring maintaining the temperature below 20° C. The agueousphase is separated and extracted twice with 20 ml of benzene. Thebenzene layer is washed to neutrality with water, then brine and driedover anhydrous sodium sulphate. The solvent is removed in vacuo to giveapproximately 30 g of oil. 12.3 g portion of the oil is dissolved in 50ml of 20% diethyl ether/80% hexane and filtered through 200 g of silicagel. Evaporation of the appropriate fractions yields 11 g. Distillationof 10 g of the obtained oil under high vacuum furnishes 8.2 g of pure1-iodo-trans-1 -octen-3-ol.

3.C. Preparation of Silyl Ethers

Resulting compounds of both Preparations 3.A and 3.B. are then submittedto Preparation 3.C. to obtain final compounds used in Preparation 4.

To a solution of 3-hydroxyoct-1-yne (see Preparation 3.A.) (2.89 g, 0.02mol), in N,N-dimethylformamide (DMF), cooled to 0° C., was addedimidazole (2.1 g), followed by tert-butyldimethylchlorosilane (3.1 g,0.02 mol), and the mixture was stirred for 3 h. Water (80 ml) and hexane(80 ml) were added; the organic layer was separated and combined with2×80 ml of hexane extractions of the aqueous layer. The solvent wasremoved (in vacuo), after drying over sodium sulfate, to give a cruderesidue (4.3 g) which was chromatographed on silica gel (80 g), elutingwith ethyl acetate-hexane (2:1, v/v) to afford3-tert-butyldimethylsilyloxyoct-1-yne. JACS, 94, 6190, (1972).

Preparation 4 Preparation of Alkynyl, Alkenyl and Alkyl Acetals ofFormula (VII) 4.A. Alkynyl Acetals 4.A.1. Octynyl Acetals

31.25 ml of n-butyl-lithium in hexane was added over 10 minutes to astirred solution of 9.9 g of 3-(t-butyldimethylsilyloxy)oct-1-yne in 30ml of toluene at 0° C. under nitrogen. After 15 minutes a 25% solutionof dimethylchloroalane in hexane (14.8 ml) was added over 0 minutes,followed, after stirring for one hour, by addition of 3.36 grams of2,3-endo-epoxyspiro[bicyclo[3.2.0]-heptane-6,2'-[1,3]dioxolan] (VI) in10 ml of toluene. The mixture was heated at 80° C. under constantstirring for 8 hours, then cooled to 0° C. and the reaction was quenchedby addition of 100 ml of saturated aqueous sodium sulfate. The mixturewas clarified by filtration and the layers separated. The aqueous layerwas extracted with ether and combined organic layers washed with water,dried with magnesium sulfate and evaporated to yield 15.15 g of an oilymixture of regioisomeric hydroxysilyoxyacetals. The oil was dissolved in100 ml of a mixture of 3:1:1 acetic acid-water-tetrahydrofuran andstirred at room temperature until TLC indicated the reaction wascomplete. The solution was neutralized with diluted NaOH, the bulk ofthe solvent was removed by evaporation, and the residue was extractedwith ether. The dried extracts were evaporated to an oily mixture of 2products in approximately 2:1 ratio, which was subsequently separated byshort column silica-gel chromatography (elution with 3%ethanol-chloroform solvent). The major component (isomer A) wasidentified as2-exo-(3-hydroxyoct-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol(VIIA), while the minor product (isomer B) is the regioisomer resultingfrom alane attack at C-3, namely3-exo-(3-hydroxyoct-1-ynyl)spiro-[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol(VIIB).

4.A.2. Other Alkynyl Acetals

Similarly, using the same procedure described in Preparation 4.A.1.,other alkynyl acetals are prepared by substituting for3-(t-butyldimethylsilyloxy)oct-1-yne the 3-silyloxy derivative of anappropriate 3-hydroxyalk-1-yne wherein said alk-1-yne has 4-15 carbonatoms.

In this manner, there are respectively obtained:

4.A.2.a.

2-exo(3-hydroxybut-1-ynyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxypent-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxyhex-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxyhept-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxynon-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxydec-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxyundec-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxydodec-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;or

2-exo(3-hydroxypentadec-1-ynyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-3-endo-ol;or

4.A.2.b.

3-exo(3-hydroxybut-1-ynyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-hydroxypent-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-hydroxyhex-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-hydroxyhept-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-hydroxynon-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-hydroxydec-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-hydroxyundec-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-hydroxydodec-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-hydroxypentadec-1-ynyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

4.A.3. Alkynyl Acetals with Side Chains Containing Branched Alkyl,Cycloalkyl, Phenyl or Substituted Phenyl Groups.

In a similar manner, but substituting

3-(t-butyldimethylsilyloxy)alk-1-yne by

3-(t-butyldimethylsilyloxy)-6-ethyloct-1-yne,

3-(t-butyldimethylsilyloxy)-3-cyclopentylprop-1-yne,

3-(t-butyldimethylsilyloxy)-3-cyclohexylprop-1-yne,

3-(t-butyldimethylsilyloxy)-3-phenylprop-1-yne,

3-(t-butyldimethylsilyloxy)3-(4-chlorophenyl)prop-1-yne,

3-(t-butyldimethylsilyloxy)-3-(2,4-dimethylphenyl)prop-1-ynyl,

3-(t-butyldimethylsilyloxy)-4-phenylbut-1-yne,

3-(t-butyldimethylsilyloxy)-4-(4-methoxyphenylbut)-1-yne, and

3-(t-butyldimethyl-silyloxy)-3-(3-trifluoromethylphenyl)prop-1-yne, thefollowing representative compounds are prepared:

4.A.3.a.

2-exo(3-hydroxy-6-ethyloct-1-ynyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxy-3-cyclopentylprop-1-ynyl))spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxy-3-cyclohexylprop-1-ynyl)spiro[bicyclo-(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxy-3-phenylprop-1-ynyl)spiro[bicyclo-(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxy-3-(4-chlorophenyl)prop-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxy-3-[2,4-dimethylphenyl]prop-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxy-4-phenylbut-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxy-4-[4-methoxyphenyl]but-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxy-3-[3-trifluoromethylphenyl]prop-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

4.A.3.b.

3-exo-(3-hydroxy-6-ethyloct-1-ynyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo-(3-hydroxy-3-cyclopentylprop-1-ynyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo-(3-hydroxy-3-cyclohexylprop-1-ynyl)spiro[bicyclo-(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo-(3-hydroxy-3-phenylprop-1-ynyl)spiro[bicyclo-(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo-(3-hydroxy-3-(4-chlorophenyl)prop-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo-(3-hydroxy-3-[2,4-dimethylphenyl]prop-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo-(3-hydroxy-4-phenylbut-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo-(3-hydroxy-4-[4-methoxyphenyl]but-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo-(3-hydroxy-3-[3-trifluoromethylphenyl]prop-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol.

4.A.4. Octynyl Acetals Containing the t-Butyldimethylsilyloxy ProtectiveGroup

Following the procedure of 4.A.1, there was obtained a mixture ofregioisomeric hydroxysilyloxyacetals, which was not hydrolyzed withacetic acid-water-tetrahydrofuran as in 4.A.1. The mixture ofhydroxysilyloxyacetals was separated using silica gel proparative columnchromatography using a mixture of 97:3 dichloromethane-acetone. Themajor component was identified as

2-exo-(3-t-butyldimethylsilyloxyoct-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)-dioxolan]-3-endo-ol,while the minor component was identified as

3-exo-(3-t-butyldimethylsilyloxyoct-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)-dioxolan]-2-endo-ol.

4.A.5. Other Alkynyl t-Butyldimethylsilyloxy Acetals

Similarly, using the same procedure described in 4.A.4., other alkynylt-butyldimethylsilyloxy acetals are prepared by substituting for3-(t-butyldimethylsilyloxy)oct-1-yne the 3-silyloxy derivative of anappropriate 3-hydroxyalk-1-yne wherein said alk-1-yne has 4-15 carbonatoms.

In this manner there are respectively obtained:

4.A.5.a.

2-exo-(3-t-butyldimethylsilyloxybut-1-ynyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo-(3-t-butyldimethylsilyloxypent-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo-(3-t-butyldimethylsilyloxyhex-1-ynyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo-(3-t-butyldimethylsilyloxyhept-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo-(3-t-butyldimethylsilyloxynon-1-ynyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo-(3-t-butyldimethylsilyloxydec-1-ynyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo-(3-t-butyldimethylsilyloxyundec-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo-(3-t-butyldimethylsilyloxydodec-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;or

2-exo-(3-t-butyldimethylsilyloxypentadec-1-ynyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-3-endo-ol;or

4.A.5.b.

3-exo-(3-t-butyldimethylsilyloxybut-1-ynyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo-(3-t-butyldimethylsilyloxypent-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo-(3-t-butyldimethylsilyloxyhex-1-ynyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo-(3-t-butyldimethylsilyloxyhept-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo-(3-t-butyldimethylsilyloxynon-1-ynyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo-(3-t-butyldimethylsilyloxydec-1-ynyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo-(3-t-butyldimethylsilyloxyundec-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo-(3-t-butyldimethylsilyloxydodec-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo-(3-t-butyldimethylsilyloxypentadec-1-ynyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

4.A.6. Alkynyl t-Butyldimethylsilyloxy Acetals with Side ChainsContaining Branched Alkyl, Cycloalkyl, Phenyl or Substituted PhenylGroups

In a similar manner but substituting

3-(t-butyldimethylsilyloxy)alk-1-yne by

3-(t-butyldimethylsilyloxy)-6-ethyloct-1-yne,

3-(t-butyldimethylsilyloxy)-3-cyclopentylprop-1-yne,

3-(t-butyldimethylsilyloxy)-3-cyclohexylprop-1-yne,

3-(t-butyldimethylsilyloxy)-3-phenylprop-1-yne,

3-(t-butyldimethylsilyloxy)3-(4-chlorophenyl)prop-1-yne,

3-(t-butyldimethylsilyloxy)-3-(2,4-dimethylphenyl)prop-1-ynyl,

3-(t-butyldimethylsilyloxy)-4-phenylbut-1-yne,

3-(t-butyldimethylsilyloxy)-4-(4-methoxyphenylbut)-1-yne, and

3-(t-butyldimethyl-silyloxy)-3-(3-trifluoromethylphenyl)prop-1-yne, thefollowing representative compounds are prepared:

4.A.6.a.

2-exo-(3-t-butyldimethylsilyloxy-6-ethyloct-1-ynyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo-(3-t-butyldimethylsilyloxy-3-cyclopentylprop-1-ynyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo-(3-t-butyldimethylsilyloxy-3-cyclohexylprop-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo-(3-t-butyldimethylsilyloxy-3-phenylprop-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo-(3-t-butyldimethylsilyloxy-3-(4-chlorophenyl)prop-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo-(3-t-butyldimethylsilyloxy-3-[2,4-dimethylphenyl]prop-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo-(3-t-butyldimethylsilyloxy-4-phenylbut-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo-(3-t-butyldimethylsilyloxy-4-[4-methoxyphenyl]but-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'(1,3)dioxolan]-3-endo-ol;

2-exo-(3-t-butyldimethylsilyloxy-3-[3-trifluoromethylphenyl]prop-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

4.A.6.b.

3-exo-(3-t-butyldimethylsilyloxy-6-ethyloct-1-ynyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo-(3-t-butyldimethylsilyloxy-3-cyclopentylprop-1-ynyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo-(3-t-butyldimethylsilyloxy-3-cyclohexylprop-1-ynyl)spiro[bicyclo-(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo-(3-t-butyldimethylsilyloxy-3-phenylprop-1-ynyl)spiro[bicyclo-(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo-(3-t-butyldimethylsilyloxy-3-(4-chlorophenyl)prop-1-ynyl)spiro-[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo-(3-t-butyldimethylsilyloxy-3-[2,4-dimethylphenyl]prop-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2' -(1,3)dioxolan]-2-endo-ol;

3-exo-(3-t-butyldimethylsilyloxy-4-phenylbut-1-ynyl)-spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo-(3-t-butyldimethylsilyloxy-4-[4-methoxyphenyl]but-1-ynyl)-spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo-(3-t-butyldimethylsilyloxy-3-[3-trifluoromethylphenyl]prop-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'(1,3)dioxolan]-2-endo-ol.

4.A.7. Octynyl Acetals via Intermediates in 4.A.4

To a stirred solution of 225 mg of2-exo-(3-t-butyldimethylsilyloxyoct-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-olin 2.5 ml tetrahydrofuran was added 2.2 ml of a 1 M solution oftetrabutylammonium fluoride in tetrahydrofuran. After 5 hours thesolvent was evaporated, water was added and the product was extractedinto ethyl acetate. Evaporation gave a residue, which was purified bysilica gel column chromatography with ethyl acetate-hexane 7:3 to give2-exo-(3-hydroyoct-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol.Similarly,3-exo-(3-hydroyoct-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-olwas prepared starting with3-exo-(3-t-butyldimethylsilyloxyoct-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol.

4.A.8. Alkynyl Acetals via Intermediates in 4.A.5

Similarly, using the procedure in 4.A.7 the list of alkynyl acetals in4.A.2 was prepared.

4.A.9. Alkynyl Acetals with Side Chains Containing Branched Alkyl,Cycloalkyl, Phenyl or Substituted Phenyl Groups via Intermediates in4.A.6

Similarly, using the procedure in 4.A.7 the list of alkynyl acetals in4.A.3. was prepared.

4.B. Alkenyl Acetals 4.B.1. Octenyl acetals

An equivalent of 1.35 M n-butyl-lithium in hexane is added to a stirredsolution of 48.2 g of 3-(t-butyldimethylsilyloxy)-trans-1-iodo-oct-1-enein anhydrous diethyl ether at -78° C. under nitrogen. After one hour asolution of 17.2 g of pent-1-ynylcopper and 45 ml ofhexamethylphosphorotriamide in ether is added. The mixture is stirredfor 2 hours at -78° C. Then, 20 g of epoxyacetal (VI) in 100 ml of etheris added dropwise over one hour. The reaction mixture is further stirredfor another 3 hours at -78° C. and then it is left for 16 hours in afreezer at -20° C. After that saturated aqueous ammonium chloride isadded and the mixture is further stirred for one hour at roomtemperature. The layers are separated and the organic layers are washedwith 200 ml of cold 2N hydrochloric acid, 200 ml of water, dried withmagnesium sulfate and evaporated. The evaporated residue is purified byshort-column chromatography on silica gel with dichloromethane aseluant. By this procedure two isomers are obtained. The major isomer is:

2-exo(3-hydroxyoct-1-trans-enyl)spiro[bicyclo(3.2.0)heptan-6,2'-(1,3)-dioxolan]-3-endo-ol.

The minor isomer is:

3-exo(3-hydroxyoct-1-trans-enyl)spiro[bicyclo(3.2.0.)heptan-6,2'-(1,3)dioxolan]-2-endo-ol.

4.B.2. Other Alkenyl Acetals

Similarly, using the same procedure described in Preparation 4.B.1.other alkenyl acetals are prepared by substituting3-(t-butyldimethylsilyloxy)trans-1-iodooct-1-ene by the appropriate3-(t-butyldimethylsilyloxy)-1-iodoalk-1-ene wherein the parent1-alken-3-ol contains 4-15 carbon atoms. (Preparation 3.C.)

In this manner, there are respectively obtained

4.B.2.a.

2-exo(3-hydroxybut-1-trans-enyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxypent-1-trans-enyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxyhex-1-trans-enyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxyhept-1-trans-enyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxynon-1-trans-enyl)spiro-[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxydec-1-trans-enyl)spiro-[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxyundec-1-trans-enyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxydodec-1-trans-enyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-3-endo-ol;or

2-exo(3-hydroxypentadec-1-trans-enyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

4.B.2.b.

3-exo(3-hydroxybut-1-trans-enyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-hydroxypent-1-trans-enyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-hydroxyhex-1-trans-enyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-hydroxyhept-1-trans-enyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-hydroxynon-1-trans-enyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-hydroxydec-1-trans-enyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-hydroxyundec-1-trans-enyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-hydroxydodec-1-trans-enyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-hydroxypentadec-1-trans-enyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol.

4.B.3. Alkynyl Acetals with Side Chains Containing Branched Alkyl,Cycloalkyl, Phenyl or Substituted Phenyl Groups

Similarly, using the same procedure described in Preparation 4.B.1.,other alkenyl acetals are prepared by substituting3-(t-butyldimethylsilyloxy)-1-iodo[oct-1-trans-ene by the appropriate3-(t-butyldimethylsilyloxy)-1-iodoalk-1-trans-ene such as

3-(t-butyldimethylsilyloxy)-1-iodo-6-ethyloct-1-trans-ene,

3-(t-butyldimethylsilyloxy)-1-iodo-3-cyclopentyl-prop-1-trans-ene,

3-(t-butyldimethylsilyloxy)-1-iodo-3-cyclohexyl-prop-1-trans-ene,

3-(t-butyldimethylsilyloxy)-1-iodo-3-phenylprop-1-trans-ene,

3-(t-butyldimethylsilyloxy)-1-iodo-3-(4-chlorophenyl)prop-1-trans-ene,

3-(t-butyldimethylsilyloxy)-1-iodo-3-(2,4-dimethylphenyl)prop-1-trans-ene,

3-(t-butyldimethylsilyloxy)-1-iodo-4-phenylbut-1-trans-ene,

3-(t-butyldimethylsilyloxy)-1-iodo-4-(4-methoxyphenyl)but-1-trans-ene,and

3-(t-butyldimethylsilyloxy)-1-iodo-3-(3-trifluoromethylphenyl)prop-1-trans-ene,the following representative compounds are prepared:

4.B.3.a.

2-exo(3-hydroxy-6-ethyloct-1-trans-enyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxy-3-cyclopentylprop-1-trans-enyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxy-3-cyclohexylprop-1-trans-enyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxy-3-phenylprop-1-trans-enyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxy-3-(4-chlorophenyl)prop-1-trans-enyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxy-3-[2,4-dimethylphenyl]prop-1-trans-enyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxy-4-phenylbut-1-trans-enyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxy-4-[4-methoxyphenylbut-1-trans-enyl)-spiro-[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxy-3-[3-trifluoromethylphenyl]prop-1-trans-enyl)spiro-[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

4.B.3.b.

3-exo(3-hydroxy-6-ethyloct-1-trans-enyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-hydroxy-3-cyclopentylprop-1-trans-enyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-hydroxy-3-cyclohexylprop-1-trans-enyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-hydroxy-3-phenylprop-1-trans-enyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-hydroxy-3-(4-chlorophenyl)prop-1-trans-enyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-hydroxy-3-[2,4-dimethylphenyl]prop-1-trans-enyl)-spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-hydroxy-4-phenylbut-1-trans-enyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-hydroxy-4-[4-methoxyphenylbut-1-trans-enyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-hydroxy-3-[3-trifluoromethylphenyl]prop-1-trans-enyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol.

4.B.4. Octenyl Acetals as Individual Diastereoisomers in the 2-endo-olSeries

A mixture of 128 mg of3-exo-(3-hydroyoct-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan-2-endo-olfrom 4.A.1, in 3 ml tetrahydrofuran was added to a stirred mixture of104 mg lithium aluminum hydride in 3 ml tetrahydrofuran under argon. Themixture was heated at reflux for 24 hours. After cooling 0.5 ml of a 2Nsodium hydroxide solution was added slowly. The precipitate was removedby filtration and was washed with 25 ml ethyl acetate. The combinedfiltrate was washed with saturated sodium chloride solution. Evaporationof solvent gave a two-component mixture that was separated by silica-gelcolumn chromatography using 70% ethyl acetate-hexane. The first elutedwas

3-exo-(3β-hydroxyoct-1-trans-enyl)spiro[bicyclo(3.2.0.)heptane-6,2'-(1,3)dioxolan]-2-endo-ol(Rf=0.34), and the second eluted was

3-exo-(3α-hydroxyoct-1-trans-enyl)spiro[bicyclo(3.2.0.)heptane-6,2'-(1,3)dioxolan]-2-endo-ol(Rf=0.25).

4.B.5. Other Alkenyl Acetals as Individual Diastereoisomers in the2-endo-ol Series

Similarly, using the same procedure described in 4.B.4, other individualdiastereoisomeric alkenyl acetals in the 2-endo-ol series are preparedby substituting the appropriate3-exo-(3-hydroxyalk-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)-dioxolan]-2-endo-oldescribed in Preparation 4.A.2.b. wherein the parent3-exo-(3-hydroxyalk-1-ynyl) side chain contains 4-15 carbon atoms.

In this manner, there are respectively obtained:

4.B.5.a.

3-exo(3β-hydroxybut-1-trans-enyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3β-hydroxypent-1-trans-enyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3β-hydroxyhex-1-trans-enyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3β-hydroxyhept-1-trans-enyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3β-hydroxynon-1-trans-enyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3β-hydroxydec-1-trans-enyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3β-hydroxyundec-1-trans-enyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3β-hydroxydodec-1-trans-enyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;or

3-exo(3β-hydroxypentadec-1-trans-enyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

4.B.5.b.

3-exo(3α-hydroxybut-1-trans-enyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3α-hydroxypent-1-trans-enyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3α-hydroxyhex-1-trans-enyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3α-hydroxyhept-1-trans-enyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3α-hydroxynon-1-trans-enyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3α-hydroxydec-1-trans-enyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3α-hydroxyundec-1-trans-enyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3α-hydroxydodec-1-trans-enyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3α-hydroxypentadec-1-trans-enyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol.

4.B.6. Individual Diasteoisomers of the 2-endo-ol Alkenyl Acetals withSide Chains Containing Branched Alkyl, Cycloalkyl, Phenyl or SubstitutedPnenyl Groups

Similarly, using the same procedure described in 4.B.4, other alkenylacetals are prepared by substituting the appropriate3-exo-(3-hydroxyalk-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-oldescribed in Preparation 4.A.3.b.

In this manner, there are respectively obtained:

4.B.6.a.

3-exo(3β-hydroxy-6-ethyloct-1-trans-enyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3β-hydroxy-3-cyclopentylprop-1-trans-enyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3β-hydroxy-3-phenylprop-1-trans-enyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3β-hydroxy-3-(4-chlorophenyl)prop-1-trans-enyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3β-hydroxy-3-[2,4-dimethylphenyl]prop-1-trans-enyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3β-hydroxy-4-phenylbut-1-trans-enyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3β-hydroxy-4-[4-methoxyphenylbut-1-trans-enyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3β-hydroxy-3-[3-trifluoromethylphenyl]prop-1-trans-enyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

4.B.6.b.

3-exo(3α-hydroxy-6-ethyloct-1-trans-enyl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3α-hydroxy-3-cyclopentylprop-1-trans-enyl)-spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3α-hydroxy-3-cyclohexylprop-1-trans-enyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3α-hydroxy-3-phenylprop-1-trans-enyl)spiro-[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3α-hydroxy-3-(4-chlorophenyl)prop-1-trans-enyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3α-hydroxy-3-[2,4-dimethylphenyl]prop-1-trans-enyl)-spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3α-hydroxy-4-phenylbut-1-trans-enyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3α-hydroxy-4-[4-methoxyphenylbut-1-trans-enyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3α-hydroxy-3-[3-trifluoromethylphenyl]prop-1-trans-enyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol.

4.C. Alkyl Acetals 4.C.1. Octyl Acetals

A solution of 1.0 g of 2-exo-(3-hydroxy-oct-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)-dioxolan]-3-endo-ol (VIIA) in 40ml ethanol is vigorously stirred in the presence of platinum (from 100mg of platinum oxide) under hydrogen at 1 atmosphere until 2 equivalentof the gas has been absorbed. The catalyst is removed by filtration.Evaporation of the filtrate under vacuum gives2-exo-(3-hydroxyoct-1-yl)spiro[(bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol.

Similarly, starting with regioisomer (VIIB)3-exo-(3-hydroxyoct-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-olis prepared.

4.C.2. Other Alkyl Acetals

Similarly, by hydrogenating the compounds of Preparation 4.A.2 accordingto the procedure of Preparation 4.C.1 the following compounds arerespectively obtained:

4.C.2.a.

2-exo(3-hydroxybut-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxypent-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxyhex-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxyhept-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxynon-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxydec-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxyundec-1-yl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxydodec-1-yl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxypentadec-1-yl)spiro[bicyclo (32.0)-heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

4.C.2.b.

3-exo(3-hydroxybut-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-hydroxypent-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-hydroxyhex-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-hydroxyhept-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-hydroxynon-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-hydroxydec-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-hydroxyundec-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-hydroxydodec-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-hydroxypentadec-1-yl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol.

4.C.3. Alkyl Acetals with Side Chains Containing Branched Alkyl,Cycloalkyl, Phenyl or Substituted Phenyl Groups

In similar manner following Procedure 4.C.1. but substituting thealkynyl acetals prepared by Procedure 4.A.3. for the octynyl acetalstarting material of the former Procedure, the following representativecompounds are prepared:

4.C.3.a.

2-exo(3-hydroxy-6-ethyloct-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxy-3-cyclopentylprop-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxy-3-cyclohexylprop-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxy-3-phenylprop-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxy-3-(4-chlorophenyl)prop-1-yl)-spiro-[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxy-3-[2,4-dimethylphenyl]prop-1-yl)spiro-[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxy-3-(4-butoxyphenyl)prop-1-yl)-spiro-[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxy-3-[4-hydroxyphenyl]prop-1-yl)-spiro-[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-hydroxy-3-[3-trifluoromethylphenyl]prop-l-yl)-spiro-[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

4.C.3.b.

3-exo(3-hydroxy-6-ethyloct-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-hydroxy-3-cyclopentylprop-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-hydroxy-3-cyclohexylprop-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-hydroxy-3-phenylprop-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-hydroxy-3-(4-chlorophenyl)prop-1-yl)spiro-[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-hydroxy-3-[2,4-dimethylphenyl]prop-1-yl)spiro-[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-hydroxy-4-phenylbut-1-yl)spiro-[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-hydroxy-4-[4-methoxyphenyl]but-lyl)spiro-[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-hydroxy-3-[3-trifluoromethylphenyl]prop-1-yl)-spiro-[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol.

4.C.4. Octyl t-Butyldimethylsilyloxy Acetals

A solution of 0.5 g of2-exo-(3-t-butyldimethylsilyloxyoct-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-olin 40 ml ethanol is vigorously stirred in the presence of platinum (from50 mg of platinum oxide) under hydrogen at 1 atmosphere until 2equivalents of gas has been absorbed. The catalyst is removed byfiltration. Evaporation of the filtrate under vacuum gives2-exo-(3-t-butyldimethylsilyloxyoct-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol.

Similarly, starting with3-exo-(3-t-butyldimethylsilyloxyoct-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-olthere is obtained3-exo-(3-t-butyldimethylsilyloxyoct-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol.

4.C.5. Other Alkyl t-Butyldimethylsilyloxy Acetals

Similarly, by hydrogenating compounds of Preparation 4.A.5 the followingcompounds are respectively obtained:

4.C.5.a.

2-exo(3-t-butyldimethylsilyloxybut-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-t-butyldimethylsilyloxypent-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-t-butyldimethylsilyloxyhex-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-t-butyldimethylsilyloxyhept-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-t-butyldimethylsilyloxynon-1-yl)-spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-t-butyldimethylsilyloxydec-1-yl)-spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-t-butyldimethylsilyloxyundec-1-yl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-3endo-ol;

2-exo(3-t-butyldimethylsilyloxydodec-1-yl)spiro-[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-t-butyldimethylsilyloxypentadec-1-yl)spiro-[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

4.C.5.b.

3-exo(3-t-butyldimethylsilyloxydroxybut-1-yl)spiro-[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-t-butyldimethylsilyloxypent-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-t-butyldimethylsilyloxyhex-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-t-butyldimethylsilyloxyhept-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-t-butyldimethylsilyloxynon-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-t-butyldimethylsilyloxydec-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-t-butyldimethylsilyloxyundec-1-yl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-t-butyldimethylsilyloxydodec-1-yl)spiro[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-t-butyldimethylsilyloxypentadec-1-yl)spiro-[bicyclo(3.2.0)-heptane-6,2'-(1,3)dioxolan]-2-endo-ol.

4.C.6. Alkyl t-Butyldimethylsilyloxy Acetals with Side Chains ContainingBranched Alkyl, Cycloalkyl, Phenyl or Substituted Phenyl Groups

Similarly, by hydrogenating compounds in Preparation 4.A.6., thefollowing representative compounds are prepared:

4.C.6.a.

2-exo(3-t-butyldimethylsilyloxy-6-ethyloct-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-t-butyldimethylsilyloxy-3-cyclopentylprop-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-t-butyldimethylsilyloxy-3-cyclohexylprop-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-t-butyldimethylsilyloxy-3-phenylprop-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-t-butyldimethylsilyloxy-3-(4-chlorophenyl)prop-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-t-butyldimethylsilyloxy-3-[2,4-dimethylphenyl]prop-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-t-butyldimethylsilyloxy-3-(4-phenylbut-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-t-butyldimethylsilyloxy-3-[4-methoxyphenylbut-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-ol;

2-exo(3-t-butyldimethylsilyloxy-3-[3-trifluoromethylphenyl]prop-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)-dioxolan]-3-endo-ol;

4.C.6.b.3-exo(3-t-butyldimethylsilyloxy-6-ethyloct-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-t-butyldimethylsilyloxy-3-cyclopentylprop-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-t-butyldimethylsilyloxy-3-cyclohexylprop-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-t-butyldimethylsilyloxy-3-phenylprop-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-t-butyldimethylsilyloxy-3-(4-chlorophenyl)prop-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-t-butyldimethylsilyloxy-3-[2,4-dimethylphenyl]prop-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-t-butyldimethylsilyloxy-4-phenylbut-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-t-butyldimethylsilyloxy-4-[4-methoxyphenyl]but-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol;

3-exo(3-t-butyldimethylsilyloxy-3-[3-trifluoromethylphenyl]prop-1-yl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol.

Preparation 5 Preparation of Bicycloheptanones by Acid Hydrolysis ofAcetals 5.A. Bicycloheptanones with Alkynyl Side Chains 5.A.1. OctynylBicycloheptanones 5.A.1.a.

A solution of 1.02 g of the octynyl acetal product isomer A of Procedure4.A.1. (VIIA) 15 ml of acetonitrile, 5.3 ml of water and 4.2 ml of 2Nsulfuric acid was stirred at ambient temperature for 16 hours. Thereaction was quenched by neutralization with aqueous sodium bicarbonateand the mixture was extracted with ethyl acetate. The extracts weredried with magnesium sulfate, evaporated to dryness and the residue waspurified by short column silica-gel chromatography. Elution with ethylacetate, gave 609 mg (96% yield) of colorless oil, homogeneous by thinlayer chromatography and giving analytical data in accord with thestructure 3-endo-hydroxy-2-exo-[3 hydroxy-oct-1-ynyl]bicyclo(3.2.0.)heptan-6-one (VIIIA).

5.A.1.b.

When octynyl acetal product isomer B of Procedure 4.A.1 (VIIB) isreacted by the same procedure, the corresponding regioisomeric ketone,namely2-endo-hydroxy-3-exo(3-hydroxy-oct-1-ynyl]bicyclo(3.2.0)heptan-6-one(VIIIB) is obtained.

5.A.2. Other Alkynyl Bicycloheptanones 5.A.2.a.

By applying the procedure of Preparation 5.A.1. to the correspondingalkynyl acetal products (VIIA) of procedure 4.A.2.a, the followingcompounds are prepared:

3-endo-hydroxy-2-exo-(3-hydroxy-but-1-ynyl)bicyclo[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxy-pent-1-ynyl)-bicyclo[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxy-hex-1-ynyl)-bicyclo[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxy-hept-1-ynyl)-bicyclo[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxy-non-1-ynyl)-bicyclo[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxy-dec-1-ynyl)-bicyclo[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxy-undec-1-ynyl)bicyclo[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxy-dodec-1-ynyl)bicyclo[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxy-pentadec-1-ynyl)bicyclo[3.2.0]heptan-6-one.

5.A.2.b.

In similar fashion, applying the procedure of Preparation 5.A.1. to therespective alkynyl acetal products (VIIB) of Procedure 4.A.2.b, thefollowing compounds were prepared:

2-endo-hydroxy-3-exo-(3-hydroxy-but-1-ynyl)bycyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxy-pent-1-ynyl)bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxy-hex-1-ynyl)bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxy-hept-1-ynyl)bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxy-non-1-ynyl)bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxy-dec-1-ynyl)-bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxy-undec-1-ynyl)bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxy-dodec-1-ynyl)bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxy-pentadec-1-ynyl)bicyclo[3.2.0]heptan-6-one.

5.A.3. Bicycloheptanones with Alkynyl Side Chains Containing BranchedAlkyl, Cycloalkyl, Phenyl or Substituted Phenyl Groups 5.A.3.a.

By employing the procedure of Preparation 5.A.1. on the alkynyl [isomer(VIIA)]products prepared by Preparation 4.A.3.a., the correspondingketones were prepared, as follows:

3-endo-hydroxy-2-exo-(3-hydroxy-6-ethyloct-1-ynyl)bicyclo[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxy-3-cyclopentylprop-1-ynyl)bicyclo[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxy-3-cyclohexylprop-1-ynyl)-bicyclo[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxy-3-phenylprop-1-ynyl)bicyclo[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxy-3-(4-chlorophenyl)prop-1-ynyl)-bicyclo[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxy-3-(2,4-dimethylphenyl)prop-1-ynyl)-bicyclo[3.2.0]heptan-6-one;

3-endo-hydroxy2-exo-(3-hydroxy-4-phenylbut-1-ynyl)bicyclo[3.2.0]heptan-6-one; PG,76

3-endo-hydroxy-2-exo-(3-hydroxy-4-(4-methoxyphenyl)but-1-ynyl)-bicyclo[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxy-3-(3-trifluoromethylphenyl)prop-1-ynyl)-bicyclo[3.2.0]heptan-6-one;

5.A.3.b.

In similar fashion, using the procedure of Preparation 5.A.1. to convertthe regioisomer (VIIB) products prepared according to procedure 4.A.3.b,the following compounds were prepared:

2-endo-hydroxy-3-exo-(3-hydroxy-6-ethyloct-1-ynyl)bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclopentylprop-1-ynyl)bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclohexylprop-1-ynyl)-bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxy-3-phenylprop-1-ynyl)bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxy-3-(4-chlorophenyl)prop-1-ynyl)-bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxy-3-(2,4-dimethylphenyl)prop-1-ynyl)-bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxy-4-phenylbut-1-ynylbicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxy-4-(4-methoxyphenylbut-1-ynyl)-bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxy-3-(3-trifluoromethylphenyl)prop-1-ynyl)-bicyclo[3.2.0]heptan-6-one;

5.A.4. Octynyl Bicycloheptanones from Hydrolysis of Octynylt-Butyldimethylsilyloxy Acetals

A solution of 0.5 g of2-exo-(3-t-butyldimethylsilyloxyoct-1-ynyl)spiro[bicyclo(3.2.0)heptan-6,2'-(1,3)dioxolan]-3-endo-ol(from Preparation 4.A.4), 7 ml of acetonitrile, 2.5 ml water, and 2.5 mlof 2N sulfuric acid was stirred at ambient temperature for 16 hours. Thereaction mixture was quenched by neutralization with aqueous sodiumbicarbonate and the mixture was extracted with ethyl acetate. Thesolution was evaporated to dryness and the residue was purified bysilica gel column chromatography with ethyl acetate-hexane 7:3 to give3-endo-hydroxy-2-exo-(3-hydroxyoct-1-ynyl)bicyclo[3.2.0]heptan-6-one.

Similarly, starting with3-exo-(3-t-butyldimethylsilyloxyoct-1-ynyl)spiro[bicyclo(3.2.0)heptan-6,2'-(1,3)dioxolan]-2-endo-ol(from Preparation 4.A.4), there was obtained2-endo-hydroxy-3-exo-(3-hydroxyoct-1-ynyl)bicyclo[3.2.0]heptan-6-one.

5.A.5. Other Alkynyl Bicycloheptanones from Hydrolysis oft-Butyldimethylsilyloxy Acetals

By applying the same procedure as 5.A.4. on the compounds in 4.A.5. thecompounds of 5.A.2 were obtained.

5.A.6. Bicycloheptanones with Alkynyl Side Chains Containing BranchedAlkyl, Cycloalkyl, Phenyl or Substituted Phenyl Groups from Hydrolysisof t-Butyldimethylsilyloxy Acetals

By applying the same procedure as 5.A.4. on the compounds in 4.A.6. thecompounds of 5.A.3 were obtained.

5.B. Bicycloheptanones with Alkenyl Side Chains 5.B.1. OctenylBicycloheptanones

By using the procedure of Preparation 5.A.1. to hydrolyze the octenylacetal products prepared according to Preparation 4.B.1, the followingcompounds are prepared:

3-endo-hydroxy-2-exo-[3-hydroxyoct-1-trans-enyl]bicyclo-(3.2.0.)heptan-6-one;

2-endo-hydroxy-3-exo(3-hydroxyoct-1-trans-enyl]bicyclo-(3.2.0)heptan-6-one.

5.B.2. Other Alkenyl Bicycloheptanones 5.B.2.a.

Similarly, employing the hydrolysis procedure of Preparation 5.A.1. onthe alkenyl acetals prepared according to procedure 4.B.2.a, thecorresponding ketones are obtained:

3-endo-hydroxy-2-exo-(3-hydroxybut-1-trans-enyl)bicyclo-[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxypent-1-trans-enyl)bicyclo-[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxyhex-1-trans-enyl)bicyclo[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxyhept-1-trans-enyl)bicyclo[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxynon-1-trans-enyl)bicyclo[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxydec-1-trans-enyl)bicyclo[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxyundec-1-trans-enyl)bicyclo-[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxydodec-1-trans-enyl)bicyclo-[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxypentadec-1-trans-enyl)bicyclo[3.2.0]heptan-6-one;

5.B.2.b.

By using the hydrolysis procedure of Preparation 5.A.1. on the isomericalkenyl acetals prepared according to procedure 4.B.2.b, the followingketones are obtained:

2-endo-hydroxy-3-exo-(3-hydroxybut-1-trans-enyl)bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxypent-1-trans-enyl)bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxyhex-1-trans-enyl)bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxyhept-1-trans-enyl)bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxynon-1-trans-enyl)bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxydec-1-trans-enyl)bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxyundec-1-trans-enyl)bicyclo-[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxydodec-1-trans-enyl)bicyclo-[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxypentadec-1-trans-enyl)bicyclo[3.2.0]heptan-6-one;

5.B.3. Bicycloheptanones with Alkenyl Side Chains Containing BranchedAlkyl, Cycloalkyl, Phenyl or Substituted Phenyl Groups 5.B.3.a.

By employing the hydrolysis procedure of Preparation 5.A.1. on thealkenyl side chain acetals prepared according to procedure 4.B.3.a, thefollowing compounds are prepared:

3-endo-hydroxy-2-exo-(3-hydroxy-6-ethyloct-1-trans-enyl)bicyclo[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxy-3-cyclopentylprop-1-trans-enyl)bicyclo[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxy-3-cyclohexylprop-1-trans-enyl)bicyclo[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxy-3-phenylprop-1-trans-enyl)bicyclo[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxy-3-(4-chlorophenyl)prop-1-trans-enyl)-bicyclo[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxy-3-(2,4-dimethylphenyl)prop-1-trans-enyl)-bicyclo[3.2.0]heptan-6-one;

3-endo-hydroxy2-exo-(3-hydroxy-4-phenylbut-1-trans-enyl)bicyclo[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxy-4-(4-methoxy)phenylbut-1-trans-enyl)-bicyclo[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxy-3-(3-trifluoromethylphenyl)prop-1-trans-enyl)-bicyclo[3.2.0]heptan-6-one;

5.B.3.b.

Similarly, subjecting the alkenyl acetal isomer (VIIB) products ofprocedure 4.B.3.b to the hydrolysis conditions of Preparation 5.A.1, thefollowing compounds are prepared:

2-endo-hydroxy-3-exo-(3-hydroxy-6-ethyloct-1-transenyl)-bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclopentylprop-1-trans-enyl)-bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclohexylprop-1-trans-enyl)-bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxy-3-phenylprop-1-trans-enyl)-bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxy-3-(4-chlorophenyl)prop-1-trans-enyl)-bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxy-3-(2,4-dimethylphenyl)prop-1-trans-enyl)-bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxy-4-phenylbut-1-trans-enyl)-bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy3-exo-(3-hydroxy-4-(4-methoxyphenyl)but-1-trans-enyl)-bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxy-3-(3-trifluoromethylphenyl)prop-1-trans-enyl)-bicyclo[3.2.0]heptan-6-one;

5.C. Bicycloheptanones with Alkyl Side Chains 5.C.1. OctylBicycloheptanones

By using the hydrolysis procedure of Preparation 5.A.1. on the octylbicycloheptane acetals prepared according to procedure of Preparation4.C.1. or 4.C.4, the following compounds are prepared:

3-endo-hydroxy-2-exo-[3 hydroxyoct-1-yl]bicyclo-(3.2.0.)heptan-6-one;

2-endo-hydroxy-3-exo[3-hydroxyoct-1-yl]bicyclo-(3.2.0)heptan-6-one.

5.C.2. Other Alkyl Bicycloheptanones 5.C.2.a.

Similarly, by using the procedure of Preparation 5.A.1. on the octylacetal products prepared according to procedure 4.C.2.a or 4.C.5, thefollowing ketones are prepared:

3-endo-hydroxy-2-exo-(3-hydroxybut-1-yl)-bicyclo[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxypent-1-yl)-bicyclo[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxyhex-1-yl)-bicyclo[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxyhept-1-yl)-bicyclo[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxynon-1-yl)-bicyclo[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxydec-1-yl)-bicyclo[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxyundec-1-yl)-bicyclo[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxydodec-1-yl)-bicyclo[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxypentadec-1-yl)bicyclo[3.2.0]heptan-6-one;

5.C.2.b.

Employing the same hydrolysis procedure of Preparation 5.A.1. on theregioisomeric alkyl acetal products (VIIB) prepared according toprocedure 4.C.2.b or 4.C.5, the following compounds are prepared:

2-endo-hydroxy-3-exo-(3-hydroxybut-1-yl)-bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxypent-1-yl)-bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxyhex-1-yl)-bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxyhept-1-yl)-bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxynon-1-yl)-bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxydec-1-yl)-bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxyundec-1-yl)-bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxydodec-1-yl)-bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxypentadec-1-yl)-bicyclo[3.2.0]heptan-6-one;

5.C.3. Bicycloheptanones with Alkyl Side Chains Containing BranchedAlkyl, Cycloalkyl, Phenyl or Substituted Phenyl Groups 5.C.3.a

Employing the hydrolysis procedure of Preparation 5.A.1. on the alkylside products prepared by chain acetal procedure 4.C.3.a or 4.C.6, thefollowing compounds are prepared:

3-endo-hydroxy-2-exo-(3-hydroxy-6-ethyloct-1-yl)bicyclo[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxy-3-cyclopentylprop-1-yl)bicyclo[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxy-3-cyclohexylprop-1-yl)bicyclo[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxy-3-phenylprop-1-yl)bicyclo[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxy-3-(4-chlorophenyl)prop-1-yl)-bicyclo[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxy-3-(2,4-dimethylphenyl)prop-1-yl)-bicyclo[3.2.0]heptan-6-one;

3-endo-hydroxy2-exo-(3-hydroxy-4-phenylbut-1-yl)bicyclo[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxy-4-(4-methoxyphenyl)but-1-yl)-bicyclo[3.2.0]heptan-6-one;

3-endo-hydroxy-2-exo-(3-hydroxy-3-(3-trifluoromethylphenyl)prop-1-yl)-bicyclo[3.2.0]heptan-6-one.

5.C.3.b.

By employing the procedure of Preparation 5.A.1. on the alkyl side chainacetals of the regioisomer (VIIB) series prepared according to procedure4.C.3.b or 4.C.6, the following ketones are prepared:

2-endo-hydroxy-3-exo-(3-hydroxy-6-ethyloct-1-yl)bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclopentylprop-1-yl)bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclohexylprop-1-yl)-bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxy-3-phenylprop-1-yl)bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxy-3-(4-chlorophenyl)prop-1-yl)-bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxy-3-(2,4-dimethylphenyl)prop-1-yl)-bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy3-exo-(3-hydroxy-(4-phenylbut-1-yl)bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxy-4-(4-methoxyphenyl)but-1-yl)-bicyclo[3.2.0]heptan-6-one;

2-endo-hydroxy-3-exo-(3-hydroxy-3-(3-trifluoromethylphenyl)prop-1-yl)-bicyclo[3.2.0]heptan-6-one.

Preparation 6 Preparation of 3-Aminooxypropionic acid

To a solution of 24 g of acetoxime in 40 ml of dioxane was added 0.4 gof sodium methoxide. The mixture was stirred at room temperature for 30minutes then cooled to 0° C. with an ice bath. 30 ml of methyl acrylatewas added, and the resulting mixture was let warm to room temperatureand stirred for 3 hours. 1N HCl was added until pH 6.8 was reached.After extractive isolation (ether), the product was purified bydistillation. Yield 8.3 g.

The oxime adduct was heated in the presence of 10 ml of 5N HCl to 60° C.until the reaction was complete (as determined by NMR spectrum of analiquot of a vacuum dried sample). The bulk of the solvent was removedunder vacuum and the product separated as white solid. Yield 2.70 g. ofthe HCl salt of 3-aminooxypropionic acid. M.P.: 151° C.

Preparation 7 Preparation of 4-Aminooxybutyric acid

10 g of benzophenone oxime was dissolved in 20 ml of dryN-methylpyrrolidone. 1.16 g of sodium was added and the mixture wasstirred at 60° C. until all sodium was dissolved. The solution was thencooled to room temperature and 4.3 g of freshly distilledγ-butyrolactone was added. The mixture was refluxed for 4 hours underconstant stirring, then concentrated under vacuum to half of itsoriginal volume and poured into 500 ml of water. Any undissolvedmaterial was removed by filtration and the solution was cooled andacidified with acetic acid. After standing one hour at room temperaturethe precipitate was collected by filtration, dissolved in acetone andtreated with Norit (activated charcoal). Cold water was added to thefiltrate until turbidity appeared and the mixture was refrigeratedovernight. More water was then added and the precipitatedN-diphenylmethylidene-aminooxybutyric acid was collected. To a solutionof 0.03 mole of N-diphenylmethylidene-aminooxybutyric acid in 100 ml of18% hydrochloric acid was added 20 ml of acetic acid, and the mixturewas successively refluxed for half an hour, cooled, washed with etherand evaporated in vacuo. The residue was dissolved in absolute ethanoland treated with Norit. Dry ether was added to the filtered solutionuntil turbidity appeared. The mixture was kept overnight at 0° C.-20° C.and the precipitated 4-aminooxybutyric acid hydrochloride was collectedand recrystallized from ethanol-ether.

Prepatation 8 Preparation of 5-Aminooxyvaleric acid

5-Aminooxyvaleric acid is prepared in the same manner using theprocedure of Preparation 6 for 4-aminooxybutyric acid except that theγ-butyrolactone is replaced by σ-valerolactone.

Preparation 9 Preparation of Individual Alkynyl Diastereoisomers 9.A.Octynyl t-Butyldimethylsilyloxy Acetals

A solution of 80 mg3-exo-(3-t-butyldimethylsilyloxyoct-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-olfrom Preparation 4.A.4 and 100 mg of dicobaltcarbonyl was stirred atambient temperature for 2 hours. The solvent was removed by evaporationand the residue was separated into two components using silica gelcolumn chromatography and eluting with acetone-dichloramethane (2:98).The first eluted was shown to be the cobalt hexacarbonyl complex of3-exo-(3α-t-butyldimethylsilyloxyoct-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol(isomer A) and the next eluted was shown to be the cobalt hexacarbonylcomplex of3-exo-(3β-t-butyldimethylsilyloxyoct-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol(isomer B). To a stirred solution of 30 mg of isomer A in 2 ml ofacetone-water (9:1) was added 120 mg of ceric ammonium nitrate. Carbonmonoxide was liberated and the red color disappeared. After 2 minutes,20 ml water was added and the mixture was extracted thoroughly withdiethyl ether. The organic extracts were combined and were extractedwith saturated sodium chloride solution. After drying over sodiumsulfate and evaporation, there was otained3-exo-(3α-t-butyldimethylsilyloxyoct-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol.

Similarly, by cleavage of isomer B there was obtained3-exo-(3β-t-butyldimethylsilyloxyoct-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol.

9.B. Other Alkynyl t-Butyldimethylsilyloxy Acetals

Similarly, following the procedure of Preparation 9.A. and using thecompounds in Preparation 4.A.5. there were obtained the individual α andβ diastereoisomers of the compounds in Preparation 4.A.5.

9.C. Alkynyl t-Butyldimethylsilyloxy Acetals with Side Chains ContainingBranched Alkyl, Cycloalkyl, Phenyl or Substituted Phenyl Groups

Similarly, following the procedure of Preparation 9.A. and using thecompounds in Preparation 4.A.6 there were obtained the individual α andβ diastereoisomers of the compounds in Preparation 4.A.6.

9.D. Octynyl Acetals

Using the procedure of 4.A.7 on the products of Preparation 9.A, therewere obtained

3-exo-(3α-hydroxyoct-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-oland

3-exo-(3β-hydroxyoct-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol.

9.E. Other Alkynyl Acetals

Similarly, using the procedure of 4.A.7 on the compounds of Preparation9.B, there were obtained the individual α and β diastereoisomers ofPreparation 4.A.2.

9.F. Alkynyl Acetals with Side Chains Containing Branched Alkyl,Cycloalkyl, Phenyl or Substituted Phenyl Groups

Similarly, using the procedure of 4.A.7 on the products of Preparation9.C, there were obtained the individual α and β diastereoisomers ofPreparation 4.A.3.

9.G. Octynyl Bicycloheptanones

Using the procedure of 5.A.4 on the products of 9.A, one obtains theindividual α and β isomers of the products of 5.A.1.

9.H. Other Alkynyl Bicycloheptanones

Using the procedure of 5.A.4. on the products of 9.B., one obtains theindividual α and β isomers of the products of 5.A.2.

9.I. Alkynyl Bicycloheptanones Containing Branched Alkyl, Cycloalkyl,Phenyl or Substituted Phenyl Groups

Using the procedure of 5.A.4 on the products of 9.C, one obtains theindividual α and β isomers of 5.A.3.

Preparation 10 Preparation of αβS-Hydroxy Side Chain Isomers 10.A.Octynyl t-Butyldimethylsilyloxy Acetals

Following the procedure of Preparation 4.A.4 usingS-3-(t-butyldimethylsilyloxy)oct-1-yne and applying the method ofPreparation 9.A, there were obtained2-exo(3αβS-t-butyldimethylsilyloxyoct-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-3-endo-oland3-exo-(3αβS-t-butyldimethylsilyloxyoct-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol.

10.B. Other alkynyl t-Butyldimethylsilyloxy Acetals

Similarly, following the procedure of Preparation 4.A.5 using theappropriate S-3-(t-butyldimethylsilyloxy)alk-1-yne and applying themethod of Preparation 9.B, αβS-t-butyldimethylsilyloxy compounds of4.A.5 were obtained.

10.C. Alkynyl t-Butyldimethylsilyloxy Acetals with Side ChainsContaining Branched Alkyl, Cycloalkyl, Phenyl or Substituted PhenylGroups

Similarly, following the procedure of 4.A.6 using the appropriateS-3-(t-butyldimethylsilyloxy)alk-1-yne and applying the method ofPreparation 9.C, the αβS-t-butyldimethylsilyloxy compounds of 4.A.6 wereobtained.

10.D. Octynyl Acetals

Using the procedure of 4.A.7 on the products of 10.A, there was obtained3-exo-(3αβS-hydroxyoct-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol.

10.E. Other Alkynyl Acetals

Similarly, using the procedure of 4.A.7 on the products of 10.B, therewere obtained the αβS-isomers of the products of 4.A.2.

10.F. Alkynyl Acetals with Side Chains Containing Branched Alkyl,Cycloalkyl, Phenyl or Subtstituted Phenyl Groups

Similarly, using the procedure of 4.A.7 on the products of 10.C, therewere obtained αβS-isomers of the products of 4.A.3.

10.G. Octynyl Bicycloheptanones

Using the procedure of Preparation of 5.A.4 on the products of 10.A, oneobtains the individual αβS-isomers of the products of 5.A.1.

10.H. Other Alkynyl Bicycloheptanones

Using the procedure of Preparation 5.A.4 on the products of 10.B, oneobtains the αβS-isomers of the products of 5.A.2.

10.I. Alkynyl Bicycloheptanones with Side Chains Containing BranchedAlkyl, Cycloalkyl, Phenyl or Substituted Phenyl Groups

Using the procedure of 5.A.4 on the products of 10.C, one obtains theαβS-isomers of the products of 5.A.3.

Preparation 11

Preparation of αS-Hydroxy Side Chain Isomers 11.A. Octynylt-Butyldimethylsilyloxy Acetals

Following the procedure of Preparation 9.A, using the products ofPreparation 10.A, one obtains3-exo-(3αS-t-butyldimethylsilyloxyoct-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol.

11.B. Other Alkynyl t-Butyldimethylsilyloxy Acetals

Following the procedure of Preparation 9.B using the products ofPreparation 10.B, one obtains the 3αS-isomers of 4.A.5.

11.C. Alkynyl t-Butyldimethylsilyloxy Acetals with Side ChainsContaining Branched Alkyl, Cycloalkyl, Phenyl or Substituted Phenyl

Following the procedure of Preparation 9.C using the products ofPreparation 10.C, one obtains the 3αS-isomers of 4.A.6.

11.D. Octynyl Acetals

Using the procedure of Preparation 4.A.7 on the products of 11.A, therewas obtained3-exo-(3αS-hydroxyoct-1-ynyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol.

11.E. Other Alkynyl Acetals

Using the procedure of Preparation 4.A.7 on the products of 11.B, therewere obtained the 3αS-isomers of the products of 4.A.2.

11.F. Alkynyl Acetals with Side Chains Containing Branched Alkyl,Cycloalkyl, Phenyl or Substituted Phenyl Groups

Using the procedure of Preparation 4.A.7 on the products of 11.C, therewere obtained the 3αS-isomers of the products of 4.A.3.

11.G. Octynyl Bicycloheptanones

Using the procedure of Preparation 5.A.4 on the products of 11.A, oneobtains2-endo-hydroxy-3-exo-(3αS-hydroxyoct-1-ynyl)bicyclo[3.2.0]heptan-6-one.

11.H. Other Alkynyl Bicycloheptanones

Using the procedure of Preparation 5.A.4 on the products of 11.B, oneobtains the 3αS isomers of the products of 5.A.2.

11.I. Alkynyl Bicycloheptanones with Side Chains Containing BranchedAlkyl, Cycloalkyl, Phenyl or Substituted Phenyl Groups

Using the procedure of Preparation 5.A.4 on the products of 11.C, oneobtains the 3αS-isomers of the products of 5.A.3.

Preparation 12 Preparation of 3αS-Hydroxyoct-1-trans-enyl Side Chain12.A. Octenyl Acetal

Using the procedure of Preparation 4.B.4 on the products of Preparation11.D gave 3-exo-(3αS-hydroxyoct-1-trans-enyl)spiro[bicyclo(3.2.0)heptane-6,2'-(1,3)dioxolan]-2-endo-ol.

12.B. Octenyl Bicycloheptanone

Using the procedure Preparation 5.A.1 on the products of Preparation12.A gave2-endo-3-exo-(3αS-hydroxyoct-1-trans-enyl)bicyclo[3.2.0]-heptan-6-one.

EXAMPLE 1 Alkynyl Aminooxypropionic Acids of Formula (1)

A. This example illustrates a method, according to the invention, ofpreparing a compound of the invention having the formulaN-[3-endo-hydroxy-2-exo-(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid (1).

1. A mixture of 80 mg3-endo-hydroxy-2-exo-(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-one(VIIIA) (Preparation 5.A.1.a.) and 53 mg of sodium acetate weredissolved in 4 ml of methanol and added to a solution of 68 mg of3-aminooxypropionic acid hydrochloric acid salt (Preparation 6)dissolved in 2 ml of methanol. The reaction mixture was stirred at roomtemperature for one hour and at which time completeness of the reactionwas confirmed by thin layer chromatography using methylenechloride-methanol-acetic acid (92:7.5:0.5). After evaporation of thesolvent, the residue was extracted several times with ethyl acetate andthe combined extracts were washed several times with saturated aqueoussalt solution, dried over magnesium sulfate, and evaporated underreduced pressure to furnish a crystalline residue of the desiredN-[3-endo-hydroxy-2-exo-(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid, purified by recrystallization from ethylacetate-heptane. Meltingpoint.: 81° C.-83° C.

B. Similarly, by following the procedure of Example 1.A.1. butsubstituting3-endo-hydroxy-2-exo-(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-one bythe corresponding alkynyl bicycloheptanone isomer (A) chosen fromcompounds prepared in Preparation 5.A.2.a, the following compounds areprepared

N-[3-endo-hydroxy-2-exo-(3-hydroxybut-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxypent-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxyhex-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxyhept-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxynon-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxydec-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxyundec-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxydodec-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid.

C. In a similar manner by following the procedure of Example 1.A.1. butemploying in place of3-endohydroxy-2-exo-(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-one thecorresponding alkynyl bicycloheptanone isomer (A) chosen from thosecompounds prepared and listed in Preparation 5.A.3.a. the followingrepresentative compounds are prepared:

N-[3-endo-hydroxy-2-exo-(3-hydroxy-6-ethyloct-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxy-3-cyclopentylprop-1ynyl)-bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxy-3-cyclohexylprop-1ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxy-3-phenylprop-1ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxy-3-(4-chlorophenyl)prop-1-ynyl)-bicyclo[3.2.0]hept-6-ylidene]3-aminooxypropionicacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxy-3-(2,4-dimethylphenyl)prop-1-ynyl)-bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxy-(4-phenylbut-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxy-4-(4-methoxyphenyl)-but-1-ynyl)-bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxy-3-(3-trifluoromethylphenyl)prop-1-ynyl)-bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid.

EXAMPLE 2 Alkenyl Aminooxypropionic Acid of Formula (1)

A. This example illustrates a method, according to the invention, ofpreparing a compound of the invention, namelyN-[3-endo-hydroxy-2-exo-(3-hydroxyoct-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid. This compound is prepared by following the procedure of Example1.A.1, but employing, in place of3-endo-hydroxy-2-exo-(3-hydroxyoct-1-ynyl)bicyclo[3.2.0]heptan-6-oneused therein3-endo-hydroxy-2-exo-(3-hydroxy-oct-1-trans-enyl)bicyclo[3.2.0]heptan-6-oneprepared according to Preparation 5.B.1.a.

B. Similarly, by following the procedure of Example 1.A.1, butsubstituting for3-endo-hydroxy-2-exo-(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-onethe corresponding alkenyl bicycloheptanone prepared according toPreparation 5.B.2.a., the following compounds are prepared:

N-[3-endo-hydroxy-2-exo-(3-hydroxybut-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxypent-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxyhex-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxyhept-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxynon-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxydec-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxyundec-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxydodec-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid.

C. In a similar manner by following the procedure of Example 1.A.1, butsubstituting3-endo-hydroxy-2-exo-(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-one bythe corresponding alkenyl bicycloheptanone products prepared inPreparation 5.B.3.a., the following representative oxime ethers areprepared:

N-[3-endo-hydroxy-2-exo-(3-hydroxy-6-ethyloct-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxy-3-cyclopentylprop-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxy-3-cyclohexylprop-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxy-3-phenylprop-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxy-3-(4-chlorophenyl)prop-1-trans-enyl)-bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxy-3-(2,4-dimethylphenyl)prop-1-trans-enyl)-bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[3-endo-hydroxy2-exo-(3-hydroxy-4-phenylbut-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxy-4-(4-methoxyphenylbut-1-trans-enyl)-bicyclo[3.2.0]hept-6-ylidene]3-aminooxypropionicacid; and

N-[3-endo-hydroxy-2-exo-(3-hydroxy-3-(3-trifluoromethylphenyl)prop-1-trans-enyl)-bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid.

EXAMPLE 3 Alkyl Aminooxypropionic Acid of Formula (1)

A. This example illustrates a method, according to the invention, ofpreparing a compound of the invention, namelyN-[3-endo-hydroxy-2-exo-(3-hydroxyoct-1-yl)-bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid. This compound is prepared by following the procedure of Example1.A.1, but substituting3-endo-hydroxy-2-exo-(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-one by3-endo-hydroxy-2-exo-(3-hydroxy-oct-1-yl)bicyclo[3.2.0]heptan-6-one asprepared in Preparation 5.C.1.a.

B. Similarly, by following the procedure of Example 1.A.1. butsubstituting3-endo-hydroxy-2-exo-(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-one bythe corresponding alkyl bicycloheptanone listed in Preparation 5.C.2.a.,the following alkyl chain oxime ethers are prepared:

N-[3-endo-hydroxy-2-exo-(3-hydroxybut-1-yl)-bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxypent-1-yl)-bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxyhex-1-yl)-bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxyhept-1-yl)-bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxynon-1-yl)-bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxydec-1-yl)-bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxyundec-1-yl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxydodec-1-yl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid.

C. In a similar manner by following the procedure of Example 1.A.1, butsubstituting3-endo-hydroxy-2-exo-(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-one bythe corresponding alkyl chain bicycloheptanones listed in Preparation5.C.3.a., the following representative substituted alkyl chain analoguesare prepared:

N-[3-endo-hydroxy-2-exo-(3-hydroxy-6-ethyloct-1-yl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxy-3-cyclopentylprop-1-yl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxy-3-cyclohexylprop-1-yl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxy-3-phenylprop-1-yl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxy-3-(4-chlorophenyl)prop-1-yl)-bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxy-3-(2,4-dimethylphenyl)prop-1-yl)-bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[3-endo-hydroxy2-exo-(3-hydroxy-4-phenylbut-1-yl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxy-4-(4-methoxyphenylbut-1-yl)-bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxy-3-(3-trifluoromethylphenyl)prop-1-yl)-bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid.

EXAMPLE 4 Alkynyl Aminooxybutyric Acid of Formula (1)

A. This example illustrates a method, according to the invention, ofpreparing a compound of the invention, namelyN-[3-endo-hydroxy-2-exo-(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0)hept-6-ylidene]-4-aminooxybutyricacid (1).

1. One equivalent of3-endo-hydroxy-2-exo-(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0)heptan-6-one(VIIIA)(Preparation 5.A.1.a.) and two equivalents of sodium acetate weredissolved in 3 ml of methanol and added to the solution of one and onehalf equivalent of 4-aminooxybutyric acid hydrochloric acid saltdissolved in 3 ml of methanol. The reaction mixture was stirred at roomtemperature for one hour at which time completeness of the reaction wasdetermined by thin layer chromatography. The residue remaining afterevaporation of the solvent was extracted several times with ethylacetate, the combined extracts washed several times with saturatedaqueous salt solution, dried over magnesium sulfate, and evaporated invacuo to furnish a solid residue of the desired product. Reprecipitationfrom ethyl acetate-heptane gave the pure title compound as a glass.

B. Similarly, by following the procedure of Example 4.A.1. butsubstituting for3-endo-hydroxy-2-exo-(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-onethe corresponding alkynyl bicycloheptanone isomer (A) chosen from thosecompounds listed in Preparation 5.A.2.a., the following compounds areobtained:

N-[3-endo-hydroxy-2-exo-(3-hydroxybut-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxypent-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxyhex-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxyhept-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxynon-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxydec-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxyundec-1-ynyl)bicyclo-[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxydodec-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid.

C. In a similar manner by following the procedure of Example 4.A.1. butsubstituting for3-endo-hydroxy-2-exo-(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-onethe corresponding alkynylbicycloheptanones prepared according toPreparation 5.A.3.a, the following representative compounds areprepared:

N-[3-endo-hydroxy-2-exo-(3-hydroxy-6-ethyloct-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxy-3-cyclopentylprop-1-ynyl)-bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxy-3-cyclohexylprop-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxy-3-phenylprop-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxy-3-(4-chlorophenyl)prop-1-ynyl)-bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxy-3-(2,4-dimethylphenyl)prop-1-ynyl)-bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[3-endo-hydroxy2-exo-(3-hydroxy-4-phenylbut-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxy-4-(4-methoxyphenylbut-1-ynyl)-bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxy-3-(3-trifluoromethylphenyl)prop-1-ynyl)-bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid.

EXAMPLE 5 Alkenyl Aminooxybutryric Acid of Formula (1)

A. This example illustrates a method, according to the invention, ofpreparing a novel compound of the invention, namelyN-[3-endo-hydroxy-2-exo-(3-hydroxyoct-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid. This compound is prepared by following the procedure of Example4.A.1. but substituting3-endo-hydroxy-2-exo-(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-one by3-endo-hydroxy-2-exo-(3-hydroxyoct-1-trans-enyl)bicyclo[3.2.0]heptan-6-oneprepared according to Procedure 5.B.1.a.

B. Similarly, by following the procedure of Example 4.A.1. butsubstituting for3-endo-hydroxy-2-exo-(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-onethe corresponding alkenyl bicycloheptanones chosen from those listed inProcedure 5.B.2.a, the following compounds are prepared:

N-[3-endo-hydroxy-2-exo-(3-hydroxybut-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxypent-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxyhex-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxyhept-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxynon-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxydec-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid

N-[3-endo-hydroxy-2-exo-(3-hydroxyundec-1-transenyl)bicyclo-[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxydodec-1-transenyl)bicyclo-[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid.

C. In a similar manner by following the procedure of Example 4.A.1. butsubstituting for3-endo-hydroxy-2-exo-(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-onethe corresponding alkenyl bicycloheptanone prepared acccording toProcedure 5.B.3.a., the following representative derivatives of4-aminooxybutyric acid are prepared:

N-[3-endo-hydroxy-2-exo-(3-hydroxy-6-ethyloct-1-transenyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxy-3-cyclopentylprop-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxy-3-cyclohexylprop-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxy-3-phenylprop-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxy-3-(4-chlorophenyl)prop-1-trans-enyl)-bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxy-3-(2,4-dimethylphenyl)prop-1-trans-enyl)-bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[3-endo-hydroxy2-exo-(3-hydroxy-4-phenylbut-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxy-4-(4-methoxyphenylbut-1-trans-enyl)-bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxy-3-(3-trifluoromethylphenyl)prop-1-trans-enyl)-bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid.

EXAMPLE 6 Alkyl Aminooxybutyric Acid of Formula (1)

A. This example illustrates a method, according to the invention, ofpreparing a novel compound of the invention, namelyN-[3-endo-hydroxy-2-exo-(3-hydroxyoct-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid. This compound is prepared by following the procedure of Example4.A.1, but substituting3-endohydroxy-2-exo-(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-one by3-endo-hydroxy-2-exo-(3-hydroxyoct-1-yl)bicyclo[3.2.0]heptan-6-oneprepared according to Procedure 5.C.1.a.

B. Similarly, by following the procedure of Example 4.A.1. butsubstituting for3-endo-hydroxy-2-exo-(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-onethe corresponding alkyl chain bicycloheptanone chosen from those listedin Procedure 5.C.2.a., the following compounds are prepared:

N-[3-endo-hydroxy-2-exo-(3-hydroxybut-1-yl)-bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxypent-1-yl)-bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxyhex-1-yl)-bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxyhept-1-yl)-bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxynon-1-yl)-bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxydec-1-yl)-bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxyundec-1-yl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxydodec-1-yl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid.

C. In a similar manner by following the procedure of Example 4.A.1. butsubstituting for3-endo-hydroxy-2exo-(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-one thecorresponding alkyl side chain bicycloheptanones chosen from compoundsprepared by Preparation 5.C.3.a., the following representative alkyloxime ethers are prepared:

N-[3-endo-hydroxy-2-exo-(3-hydroxy-6-ethyloct-1-yl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxy-3-cyclopentylprop-1-yl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxy-3-cyclohexylprop-1-yl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxy-3-phenylprop-1-yl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxy-3-(4-chlorophenyl)prop-1-yl)-bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxy-3-(2,4-dimethylphenyl)prop-1-yl)-bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyric acid;

N-[3-endo-hydroxy2-exo-(3-hydroxy-4-phenylbut-1-yl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[3-endo-hydroxy-2-exo-(3-hydroxy-4-(4-methoxyphenylbut-1-yl)-bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid; and

N-[3-endo-hydroxy-2-exo-(3-hydroxy-3-(3-trifluoromethylphenyl)prop-1-yl)-bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid.

EXAMPLE 7 Alkynyl Aminooxypropionic Acid of Formula (2)

A. This example illustrates a method, according to the invention, ofpreparing the novel compound of the invention having the structureN-[2-endo-hydroxy-3-exo-(3-hydroxyoct-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionic acid (2).

1. A mixture of 80 mg of2-endo-hydroxy-3-exo-(3-hydroxyoct-1-ynyl)bicyclo[3.2.0]heptan-6-one(VIIIB) (Preparation 5.A.1.b.) and 53 mg of sodium acetate weredissolved in 4 ml of methanol and added to a solution of 68 mg of3-aminooxypropionic acid hydrochloric acid salt (Preparation 5)dissolved in 3 ml of methanol.

The reaction mixture was stirred at room temperature for one hour andcompleteness of the reaction was determined by thin layer chromatographyusing methylene chloride-methanol-acetic acid (97:7.5:0.5). Afterevaporation of the solvent the resulting residue was extracted severaltimes with ethyl acetate, the combined extracts washed several timeswith saturated aqueous salt solution, dried over magnesium sulfate, andevaporated to obtain a residue of the desired 3-aminooxypropionic acidderivative. Reprecipitation from ethyl acetate-heptane furnishedchromatographically pureN-[2-endo-hydroxy-3-exo-(3-hydroxyoct-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid as a glassy solid whose C.I.M.S. contained an MH⁺ peak at m/e 338.

A.2. Similarly, using the procedure of Example 7.A.1 and using2-endo-hydroxy-3-exo(3αβS-hydroxyoct-1-ynyl)bicyclo[3.2.0]heptan-6-one(Preparation 10.G), one obtainsN-[2-endo-hydroxy-3-exo-(3αβS-hydroxyoct-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid as a glassy solid, whose C.I.M.S. contained an MH⁺ peak at m/e 338and an MNH₄ ⁺ peak at m/e 355.

A.3. Similarly, using the procedure of Example 7.A.1 and using2-endo-hydroxy-3-exo(3αS-hydroxyoct-1-ynyl)bicyclo[3.2.0]heptan-6-one,one obtainsN-[2-endo-hydroxy-3-exo-(3αS-hydroxyoct-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid as a glassy solid, whose C.I.M.S. contained an MH⁺ peak at m/e 338and whose [α]_(D) was -136° (methanol).

B.1. Similarly, by following the procedure of Example 7.A.1. butsubstituting for2-endo-hydroxy-3-exo-(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-onethe corresponding alkynyl bicycloheptanone isomer (B) products ofPreparation 5.A.2.b., the following compounds are prepared, amongothers:

N-[2-endo-hydroxy-3-exo-(3-hydroxybut-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxypent-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxyhex-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxyhept-1-ynyl)bicyclo[-3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxynon-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxydec-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid, a glass whose C.I.M.S. contains a MH⁺ peak at m/e 366;

N-[2-endo-hydroxy-3-exo-(3-hydroxyundec-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxydodec-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid.

C. In a similar manner by following the procedure of Example 7.A.1, butsubstituting for2-endo-hydroxy-3-exo-(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-onethe corresponding alkynyl bicycloheptanone isomer (B) products chosenfrom those listed in Preparation 5.A.3.b., the following representativeoxime ethers of structure (2) are prepared:

N-[2-endo-hydroxy-3-exo-(3-hydroxy-6-ethyloct-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclopentylprop-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid, whose C.I.M.S. has an MH⁺ peak at m/e 336;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclohexylprop-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid, whose C.I.M.S. has an MH⁺ peak at m/e 350 and MNH⁺ peak at m/e367;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-phenylprop-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-(4-chlorophenyl)prop-1-ynyl)-bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-(2,4-dimethylphenyl)prop-1-ynyl)-bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy3-exo-(3-hydroxy-4-phenylbut-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-4-(4-methoxyphenylbut-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-(3-trifluoromethylphenyl)prop-1-ynyl)-bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid.

EXAMPLE 8 Alkenyl Aminooxypropionic Acid of Formula (2).

A.1. This example illustrates a method, according to the invention, ofpreparing the compound of the formulaN-[2-endo-hydroxy-3-exo-(3-hydroxy-oct-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid. This compound is prepared by following the procedure of Example7.A.1, but substituting2-endo-hydroxy-3-exo-(3-hydroxyoct-1-ynyl)-bicyclo[3.2.0]heptan-6-one(VIIIB) with2-endo-hydroxy-3-exo-(3-hydroxyoct-1-trans-enyl)bicyclo[3.2.0]heptan-6-one,according to the Preparation 5.B.1.b.

A.2. Following the procedure of Example 7.A.1, but substituting2-endo-hydroxy-3-exo-(3-hydroxyoct-1-ynyl)bicyclo[3.2.0]-heptan-6-onewith2-endo-hydroxy-3-exo-(3αS-hydroxyoct-1-trans-enyl)bicyclo[3.2.0]heptan-6-one(Preparation 12.B), one obtainsN-[2-endo-hydroxy-3-exo-(3αS-hydroxyoct-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid, a glass whose C.I.M.S. contains an MH⁺ peak at m/e 340.

B. Similarly, by following the procedure of Example 7.A.1. butsubstituting2-endo-hydroxy-3-exo-(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-one bycorresponding alkenyl bicycloheptanone isomers (B) prepared according toProcedure 5.B.2.b, the following compounds are prepared:

N-[2-endo-hydroxy-3-exo-(3-hydroxy-but-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-pent-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-hex-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-hept-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-non-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-dec-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-undec-1-trans-enyl)bicyclo-[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-dodec-1-trans-enyl)bicyclo-[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid.

C.1. In a similar manner by following the procedure of Example 7.A.1,but substituting2-endo-hydroxy-3-exo(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-one bycorresponding alkenyl bicycloheptanone chosen from those listed in thePreparation 5.B.3.b, the following representative compounds areprepared:

N-[2-endo-hydroxy-3-exo-(3-hydroxy-6-ethyloct-1-transenyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclopentylprop-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionic acid, whose C.I.M.S. contained an MH⁺ peak at m/e 338;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclohexylprop-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid, whose C.I.M.S. contained an MH⁺ peak at m/e 352 and an MNH₄ ⁺ peakat m/e 369;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-phenylprop-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-(4-chlorophenyl)prop-1-trans-enyl)-bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2endo-hydroxy-3-exo-(3-hydroxy-3-(2,4-dimethylphenyl)prop-1-trans-enyl)-bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy3-exo-(3-hydroxy-4-phenylbut-1-trans-enyl)-bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-4-(4-methoxyphenylbut)prop-1-trans-enyl)-bicyclo[3.2.0]hept-6-ylidene]3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-(3-trifluoromethylphenyl)prop-1-trans-enyl)-bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid.

EXAMPLE 9

Alkyl Aminooxypropionic Acid of Formula (2)

A. This example illustrates a method, according to the invention, ofpreparing the compound of the formulaN-[2-endo-hydroxy-3-exo-(3-hydroxy-oct-1-yl)-bicyclo[3.2.0)hept-6-ylidene]-3-aminooxypropionicacid.

This compound is prepared by following the procedure of Example 7.A.1,but substituting2-endo-hydroxy-3-exo-(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-one(VIIIB) with2-endo-hydroxy-3-exo-(3-hydroxy-oct-1-yl)bicyclo-[3.2.0]heptan-6-oneprepared according to Procedure 5.C.1.b, a glass whose C.I.M.S.contained an MH⁺ peak at m/e 342.

B. Similarly, by following the procedure of Example 7.A.1. butsubstituting 2-endo-hydroxy-3-exo(3-hydroxy-oct-1-ynyl)bicyclo-[3.2.0]heptan-6-one by thecorresponding alkyl bicycloheptanone chosen from those listed inPreparation 5.C.2.b, the following compounds are prepared:

N-[2-endo-hydroxy-3-exo-(3-hydroxy-but-1-yl)bicyclo-[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-pent-1-yl)bicyclo-[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-hex-1-yl)bicyclo-[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-hept-1-yl)bicyclo-[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-non-1-yl)bicyclo-[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-dec-1-yl)bicyclo-[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid, a glass whose C.I.M.S. contained an MH⁺ peak at m/e 370;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-undec-1-yl)bicyclo-[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-dodec-1-yl)bicyclo-[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid.

C. In a similar manner by following the procedure of Example 7.A.1. butsubstituting2-endo-hydroxy-3-exo(3-hydroxy-oct-1-yl)bicyclo-[3.2.0]heptan-6-one bythe corresponding alkyl bicycloheptanones listed in the Preparation5.C.3.b. the following representative compounds are prepared:

N-[2-endo-hydroxy-3-exo-(3-hydroxy-6-ethyloct-1-yl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclopentylprop-1-yl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid, a glass whose C.I.M.S. contained an MH⁺ peak at m/e 340;

N-[2-end-hydroxy-3-exo-(3-hydroxy-3-cyclohexylprop-1-yl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid, a glass whose C.I.M.S. contained an MH⁺ peak at m/e 354;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-phenylprop-1-yl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-(4-chlorophenyl)prop-1-yl)-bicyclo[3.2.0]hept-6-ylidene]3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-(2,4-dimethylphenyl)prop-1-yl)-bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy3-exo-(3-hydroxy-4-phenylbut1-yl)-bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-(3-trifluoromethylphenyl)prop-1-yl)-bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-4-(4-methoxyphenylbut-1-yl)-bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid.

EXAMPLE 10 Alkynyl Aminooxybutyric Acid of Formula (2)

A. This example illustrates a method, according to the invention, ofpreparing the compound of the formula (2),N-[2-endo-hydroxy-3-exo-(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid.

1. 0.32 mmole of2-endo-hydroxy-3-exo(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-one(VIIB)(Preparation 5.A.1.b.) and 0.64 mmole of sodium acetate weredissolved in 3 ml of methanol and added to a solution of 0.48 mmole of4-aminooxybutyric acid hydrochloric acid salt (Preparation 6) in 3 ml ofmethanol. The reaction mixture was stirred at room temperature for onehour and completeness of the reaction was determined by thin layerchromatography. The solvent was evaporated from the reaction mixture.The residue was extracted several times with ethyl acetate, the combinedextracts were washed several times with saturated aqueous salt solution,dried over magnesium sulfate and evaporated in vacuo to provide acrystalline residue of the desired product. Recrystallization from ethylacetate-heptane furnished pure crystallineN-[2-endo-hydroxy-3-exo(3-hydroxy-oct-1-ynyl)-bicyclo-[3.2.0)hept-6-ylidene]-4-aminooxybutyricacid, m.p. 82-84° C.

B. Similarly, by following the procedure of Example 10.A.1, butsubstituting2-endo-hydroxy-3-exo(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-one bythe corresponding alkynyl bicycloheptanones prepared according toPreparation 5.A.2.b., the following compounds are prepared:

N-[2-endo-hydroxy-3-exo-(3-hydroxy-but-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-pent-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-hex-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-hept-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-non-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-dec-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-undec-1-ynyl)bicyclo-[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-dodec-1-ynyl)bicyclo-[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid.

C. In a similar manner by following the procedure of Example 10.A.1, butsubstituting2-endo-hydroxy-3-exo(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-one bycorresponding alkynyl bicycloheptanones chosen from those described inPreparation 5.A.3.b, the following representative compounds areprepared:

N-[2-endo-hydroxy-3-exo-(3-hydroxy-6-ethyloct-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclopentylprop-1-ynyl)-bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclohexylprop-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-phenylprop-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-(4-chlorophenyl)prop-1-ynyl)-bicyclo[3.2.0]hept-6-ylidene]4-aminooxybutyricacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-(2,4-dimethylphenyl)prop-1-ynyl)-bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[2-endo-hydroxy3-exo-(3-hydroxy-phenylbut-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-4-(4-methoxyphenylbut-1-ynyl)-bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-(3-trifluoromethylphenyl)prop-1-ynyl)-bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid.

EXAMPLE 11 Alkenyl Aminooxybutyric Acid of Formula (2)

A. This example illustrates a method, according to the invention, ofpreparing compounds of the formulaN-[2-endo-nydroxy-3-exo-(3-hydroxy-oct-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyric acid. This compound isprepared by following the procedure of Example 10.A.1, but substituting2-endo-hydroxy-3-exo(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-onewith 2-endo-hydroxy-3-exo-(3-hydroxy-oct-1-trans-enyl)bicyclo[3.2.0]heptan-6-one prepared according to the Procedure 5.B.1.b.

B. Similarly, by following the procedure of Example 10.A.1, butsubstituting2-endo-hydroxy-3-exo(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-one bycorresponding alkenyl bicycloheptanones according to Procedure 5.B.2.b,the following compounds are prepared:

N-[2-endo-hydroxy-3-exo-(3-hydroxy-but-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-pent-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-hex-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-hept-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-non-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-dec-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-undec-1-transenyl)bicyclo-[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-dodec-1-transenyl)bicyclo-[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid.

C. In a similar manner by following the procedure of Example 10.A.1. butsubstituting2-endo-hydroxy-3-exo-(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-one bycorresponding alkenyl bicycloheptanones according to Preparation5.B.3.b, the following representative compounds are prepared:

N-[2-endo-hydroxy-3-exo-(3-hydroxy-6-ethyloct-1-transenyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclopentylprop-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclohexylprop-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-phenylprop-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-(4-chlorophenyl)prop-1-trans-enyl)-bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-(2,4-dimethylphenyl)prop-1-trans-enyl)-bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[2-endo-hydroxy3-exo-(3-hydroxy-4-phenylbut1-trans-enyl)-bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-4-(4-methoxyphenylbut-1-trans-enyl)-bicyclo[3.2.0]hept-6-ylidene]-4aminooxybutyricacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-(3-trifluoromethylphenyl)prop-1-trans-enyl)-bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyric acid.

EXAMPLE 12 Alkyl Aminooxybutyric Acid of Formula (2)

A. This example illustrates a method, according to the invention, of apreparing compound of the formulaN-[2-endo-hydroxy-3-exo-(3-hydroxy-oct-1-yl)bicyclo[3.2.0)hept-6-ylidene]-4aminooxybutyric acid. This compound is prepared by following theprocedure of Example 10.A.1, but substituting2-endo-hydroxy-3-exo(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-onewith 2-endo-hydroxy-3-exo-(3-hydroxy-oct-1-yl)bicyclo[3.2.0]heptan-6-one prepared according to the Procedure 5.C.1.b.

B. Similarly, by following the procedure of Example 10.A.1, butsubstituting2-endo-hydroxy-3-exo(3-hydroxy-oct-1-yl)bicyclo[3.2.0]heptan-6-one bythe corresponding alkyl bicycloheptanone listed in Preparation 5.C.2.b,the following compounds are prepared:

N-[2-endo-hydroxy-3-exo-(3-hydroxy-but-1-yl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-pent-1-yl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-hex-1-yl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-hept-1-yl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-non-1-yl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-dec-1-yl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-undec-1-yl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-dodec-1-yl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

C. In a similar manner by following the procedure of Example 10.A.1, butsubstituting2-endo-hydroxy-3-exo(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-one bythe corresponding alkyl bicycloheptanone chosen from compounds listed inPreparation 5.C.3.b the following representative compounds are prepared:

N-[2-endo-hydroxy-3-exo-(3-hydroxy-6-ethyloct-1-yl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclopentylprop-1-yl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclohexylprop-1-yl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-phenylprop-1-yl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-(4-chlorophenyl)-prop-oct-1-yl)-bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-(2,4-dimethylphenyl)prop-1-yl)-bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[2-endo-hydroxy3-exo-(3-hydroxy-4-phenylbut-1-yl)-bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-4-(4-methoxyphenylbut-1-yl)-bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-(3-trifluoromethylphenyl)prop-1-yl)-bicyclo[3.2.0]hept-6-ylidene]-b4-aminooxybutyric acid.

EXAMPLE 13 Alkynyl Aminooxyacetic acid of Formula (1) A. This exampleillustrates the preparation of a compound of our invention encompassedby formula (1), namely

N-3-endo-hydroxy-2-exo-(3-hydroxyoct-1-ynyl)bicyclo[3.2.0]nept-6-ylidene]-aminooxyaceticacid.

1. To a solution of octynyl bicycloheptanone VI (0.075 g) and sodiumacetate (0.031 g) in 3 ml MeOH is added 0.05 g of carboxymethoxylaminehemihydrochloride, and the mixture is stirred at room temperature untilTLC indicates essentially complete reaction (1.5 hours). The solvent isremoved under reduced pressure and the resulting residue is extractedseveral times with ethyl acetate. The combined extracts are washed withsaturated brine, dried over sodium sulfate and evaporated to furnish aresidue of crude oximino acid. Preparative chromatography employing aneluant of 90% CH₂ Cl₂, 9.7% CH₃ OH and 0.3% HOAc furnishes, from theappropriate fractions, the pure oximino acid as a glass exhibiting theanticipated spectral characteristics for the title structure. Chemicalionization mass spectroscopy (C.I.M.S.) furnishes a parent peak (MH⁺) atm/e 324.

B. Similarly, by following the procedure of Example 13.A.1, butsubstituting for3-endo-hydroxy-2-exo(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-one thecorresponding alkynyl bicycloheptanone chosen from compounds prepared inPreparation 5.A.2.a, the following compounds are prepared:

N-3-endo-hydroxy-2-exo-(3-hydroxybut-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-3-endo-hydroxy-2-exo-(3-hydroxypent-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-3-endo-hydroxy-2-exo-(3-hydroxyhex-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-3-endo-hydroxy-2-exo-(3-hydroxyhept-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-3-endo-hydroxy-2-exo-(3-hydroxynon-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-3-endo-hydroxy-2-exo-(3-hydroxydec-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-3-endo-hydroxy-2-exo-(3-hydroxyundec-1-ynyl)bicyclo-[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-3-endo-hydroxy-2-exo-(3-hydroxydodec-1-ynyl)bicyclo-[3.2.0]hept-6-ylidene]-aminooxyaceticacid; C. In a similar manner by following the procedure of Example1.A.1, but substituting for3-endo-hydroxy-2-exo-(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-onethe corresponding alkynyl bicycloheptanone isomer (A) chosen from thosecompounds described in Preparation 5.A.3.a, the following representativecompounds are prepared:

N-3-endo-hydroxy-2-exo-(3-hydroxy-6-ethyloct-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-3-endo-hydroxy-2-exo-(3-hydroxy-3-cyclopentylprop-1-ynyl)-bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-3-endo-hydroxy-2-exo-(3-hydroxy-3-cyclohexylprop--ynyl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyacetic acid;

N-3-endo-hydroxy-2-exo-(3-hydroxy-3-phenylprop-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-3-endo-hydroxy-2-exo-(3-hydroxy-3-(4-chlorophenyl)prop-oct-1-ynyl)-bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid;

N-3-endo-hydroxy-2-exo-(3-hydroxy-3-(2,4-dimethylphenyl)prop-1-ynyl)-bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-3-endo-hydroxy-2-exo-(3-hydroxy-(4-phenylbut-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-3-endo-hydroxy-2-exo-(3-hydroxy-4-(4-methoxyphenylbut-1-ynyl)-bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-3-endo-hydroxy-2-exo-(3-hydroxy-3-(3-trifluoromethylphenyl)prop-1-ynyl)-bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid.

EXAMPLE 14 Alkenyl Aminooxyacetic Acid of Formula (1)

A. This example illustrates a method, according to the invention, ofpreparing the compound of the formula

N-3-endo-hydroxy-2-exo-(3-hydroxy-oct-1-transenyl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid. This compound is prepared by following the procedure of Example13.A.1, but substituting3-endo-hydroxy-2-exo(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-onewith3-endo-hydroxy-2-exo-(3-hydroxy-oct-1-trans-enyl)bicyclo[3.2.0]heptan-6-oneprepared according to Preparation 5.B.1.a.

B. Similarly, by following the procedure of Example 13.A.1, butsubstituting3-endo-hydroxy-2-exo(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-one bythe corresponding alkenyl bicycloheptanone wherein alkenyl is chosenfrom those prepared according to Preparation 5.B.2.a, the followingcompounds are prepared

N-3-endo-hydroxy-2-exo-(3-hydroxybut-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-3-endo-hydroxy-2-exo-(3-hydroxypent-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-3-endo-hydroxy-2-exo-(3-hydroxyhex-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-3-endo-hydroxy-2-exo-(3-hydroxyhept-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-3-endo-hydroxy-2-exo-(3-hydroxynon-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-3-endo-hydroxy-2-exo-(3-hydroxydec-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-3-endo-hydroxy-2-exo-(3-hydroxyundec-1-transenyl)bicyclo-[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-3-endo-hydroxy-2-exo-(3-hydroxydodec-1-transenyl)bicyclo-[3.2.0]hept-6-ylidene]-aminooxyaceticacid; of Example 13.A.1, but substituting3-endo-hydroxy-2-exo(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-one bycorresponding alkenyl bicycloheptanone as illustrated in Preparation5.B.3.a, the following representative compounds are prepared:

N-3-endo-hydroxy-2-exo-(3-hydroxy-6-ethyloct-1-transenyl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-3-endo-hydroxy-2-exo-(3-hydroxy-3-cyclopentylprop-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-3-endo-hydroxy-2-exo-(3-hydroxy-3-cyclohexylprop-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-3-endo-hydroxy-2-exo-(3-hydroxy-3-phenylprop- 1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionic acid;

N-3-endo-hydroxy-2-exo-(3-hydroxy-3-(4-chlorophenyl)prop-1-trans-enyl)-bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid;

N-3-endo-hydroxy-2-exo-(3-hydroxy-3-(2,4-dimethylphenyl)prop-1-trans-enyl)-bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-3-endo-hydroxy-2-exo-(3-hydroxy-4-phenylbut-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-3-endo-hydroxy-2-exo-(3-hydroxy-4-(4-methoxyphenylbut-1-trans-enyl)-bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid; and

N-3-endo-hydroxy-2-exo-(3-hydroxy-3-(3-trifluoromethylphenyl)prop-1-trans-enyl)-bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid.

EXAMPLE 15 Alkyl Aminooxyacetic Acid of Formula (61)

A. This example illustrates a method, according to the invention, ofpreparing the compound having the formula

N-3-endo-hydroxy-2-exo-(3-hydroxy-oct-1-yl)bicyclo[3.2.0)hept-6-ylidene]-aminooxyaceticacid. This compound is prepared by following the procedure of Example13.A.1, but substituting for3-endo-hydroxy-2-exo(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-one the3-endo-hydroxy-2-exo-(3-hydroxy-oct-1-yl)bicyclo[3.2.0]heptan-6-oneaccording to the Preparation 5.C.1.a.

B. Similarly, by following the procedure of Example 13.A.1, butsubstituting for3-endo-hydroxy-2-exo(3-hydroxy-oct-1-yl)bicyclo[3.2.0]heptan-6-one thecorresponding alkyl bicycloheptanones listed in Preparation 5.C.2.a, thefollowing compounds are prepared:

N-3-endo-hydroxy-2-exo-(3-hydroxybut-1-yl)-bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-3-endo-hydroxy-2-exo-(3-hydroxypent-1-yl)-bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-3-endo-hydroxy-2-exo-(3-hydroxyhex-1-yl)-bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-3-endo-hydroxy-2-exo-(3-hydroxyhept-1-yl)-bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-3-endo-hydroxy-2-exo-(3-hydroxynon-1-yl)bicyclo-[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-3-endo-hydroxy-2-exo-(3-hydroxydec-1-yl)bicyclo-[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-3-endo-hydroxy-2-exo-(3-hydroxyundec-1-yl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-3-endo-hydroxy-2-exo-(3-hydroxydodec-1-yl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid; C. In a similar manner by following the procedure of Example13.A.1, but substituting3-endo-hydroxy-2-exo(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-one bycorresponding alkyl bicycloheptanones listed in Preparation 5.C.3.a, thefollowing representative compounds are prepared:

N-3-endo-hydroxy-2-exo-(3-hydroxy-6-ethyloct-1-yl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-3-endo-hydroxy-2-exo-(3-hydroxy-3-cyclopentylprop-1-yl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyacetic acid;

N-3-endo-hydroxy-2-exo-(3-hydroxy-3-cyclohexylprop-1-yl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-3-endo-hydroxy-2-exo-(3-hydroxy-3-phenylprop-1-yl)-bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-3-endo-hydroxy-2-exo-(3-hydroxy-3-(4-chlorophenyl)-prop-oct-1-yl)-bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-3-endo-hydroxy-2-exo-(3-hydroxy-3-(2,4-dimethylphenyl)prop-1-yl)-bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-3-endo-hydroxy2-exo-(3-hydroxy-4-phenylbut-1-yl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-3-endo-hydroxy-2-exo-(3-hydroxy-4-(4methoxyphenyl-but-1-yl)-bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid;

N-3-endo-hydroxy-2-exo-(3-hydroxy-3-(3-trifluoromethylphenyl)prop-1-yl)-bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid.

EXAMPLE 16 Alkynyl Aminooxyacetic Acid of Formula (2)

This example illustrates preparation of a compound of formula (2),namelyN-[2-endo-hydroxy-3-exo(3αS-hydroxyoct-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid.

In a manner analogous to that described in Example 13, but substitutingoctynyl bicycloheptanone (VII)(0.080 g) for ynone (VI) and using 0.033 gof NaOAc and 0.0525 g of carboxymethoxylamine hemihydrochloride, thecrude oxyminoacetic acid is obtained. Purification by preparative layerchromatography furnishes the pure title compound as a glass exhibitingthe anticipated spectral characteristics as well as a parent peak(C.I.M.S.) at m/e 324, [α]_(D) =-133° (methanol).

B. Similarly, by following the procedure of Example 13.A.1, butsubstituting for2-endo-hydroxy-3-exo(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-one thecorresponding alkynyl bicycloheptanone of Preparation 5.A.2.b, thefollowing compounds are prepared, among others:

N-[2-endo-hydroxy-3-exo-(3-hydroxybut-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxypent-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxyhex-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxyhept-1-ynyl)bicyclo[-3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxynon-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxydec-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid, glass, C.I.M.S. exhibits a peak MNH₄ ⁺ at m/e 369 and a peak MH⁺at m/e 352;

N-[2-endo-hydroxy-3-exo-(3-hydroxyundec-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxydodec-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid; C. In a similar manner by following the procedure of Example13.A.1. but substituting2-endo-hydroxy-3-exo(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-one bycorresponding alkynyl bicycloheptanone isomer (B) chosen from thoselisted in the Preparation 5.A.3.b., the following representativecompounds are prepared:

N-[2-endo-hydroxy-3-exo-(3-hydroxy-6-ethyloct-ynyl)-bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclopentylprop-ynyl)-bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid, a glass whose C.I.M.S. contained an MH⁺ peak at m/e 322;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclohexylprop-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid, a glass whose C.I.M.S. contained an MH+ peak at m/e 336 and anMNH⁺ peak at m/e 353;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-phenylprop-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-(4-chlorophenyl)prop-oct-1-ynyl)-bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-(2,4-dimethylphenyl)prop-1-ynyl)-bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-[2-endo-hydroxy3-exo-(3-hydroxy-4-phenylbut-1-ynyl)-bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-4-(4-methoxyphenylbut-1-ynyl)-bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-(3-trifluoromethylphenyl)prop-1-ynyl)-bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid.

EXAMPLE 17 Alkenyl Aminooxyacetic Acid of Formula (2).

A. This example illustrates a method, according to the invention, ofpreparing the compound of the formula (2),N-[2-endo-hydroxy-3-exo-(3-hydroxy-oct-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid. This compound is prepared by following the procedure of Example13.A.1. but substituting 2-endo-hydroxy-3-exo-(3αS-hydroxyoct-1-ynyl)bicyclo[3.2.0]heptan-6-one (VIIIB) with2-endo-hydroxy-3-exo-(3αS-hydroxy-oct-1-trans-enyl)bicyclo[3.2.0]heptan-6-one, according to the Preparation 5.B.1.b, a glass whoseC.I.M.S. contained an MH⁺ peak at m/e 326.

B. Similarly, by following the procedure of Example 13.A.1, butsubstituting for2-endo-hydroxy-3-exo(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-one thecorresponding alkenyl bicycloheptanones isomer (B) according toProcedure 5.B.2.b, the following compounds are prepared:

N-[2-endo-hydroxy-3-exo-(3-hydroxybut-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxypent-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxyhex-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxyhept-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxynon-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxydec-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxyundec-1-trans-enyl)bicyclo-[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxydodec-1-trans-enyl)bicyclo-[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

C. In a similar manner by following the procedure of Example 13.A.1, butsubstituting for2-endo-hydroxy-3-exo-(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-onethe corresponding alkenyl bicycloheptanones chosen from those listed inthe Preparation 5.B.3.b, the following representative compounds areprepared:

N-[2-endo-hydroxy-3-exo-(3-hydroxy-6-ethyloct-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclopentylprop-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid, a glass whose C.I.M.S. contained an MH⁺ peak at m/e 324;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclohexylprop-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-phenylprop-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-(4-chlorophenyl)prop-oct-1-trans-enyl)-bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-(2,4-dimethylaminooxyacetic acid;

N-[2-endo-hydroxy3-exo-(3-hydroxy-4-phenylbut-1-trans-enyl)-bicyclo[3.2.0]hept-6-ylidene]-amino-oxyacetic acid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-4-(4-methoxyphenylbut-1-trans-enyl)-bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-(3-trifluoromethylphenyl)prop-1-trans-enyl)-bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid.

EXAMPLE 18 Alkyl Aminooxyacetic Acid of Formula (2).

A. This example illustrates a method, according to the invention, ofpreparing the compound of the formula (2),N-[2-endo-hydroxy-3-exo-(3-hydroxy-oct-1-yl)557bicyclo[3.2.0)hept-6-ylidene]-aminooxyacetic acid.

This compound is prepared by following the procedure of Example 13.A.1,but substituting2-endo-hydroxy-3-exo(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-one(VIIIB) with2-endo-hydroxy-3-exo-(3-hydroxy-oct-1-yl)bicyclo[3.2.0]heptan-6-oneaccording to Procedure 5.C.1.b, a glass whose C.I.M.S. contained an MH⁺peak at m/e 328.

B. Similarly, by following the procedure of Example 13.A.1, butsubstituting for2-endo-hydroxy-3-exo(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]heptan-6-one thecorresponding alkyl bicycloheptanones chosen from those listed inPreparation 5.C.2.b, the following compounds are prepared:

N-[2-endo-hydroxy-3-exo-(3-hydroxybut-1-yl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxypent-1-yl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxyhex-1-yl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxyhept-1-yl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxynon-1-yl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxydec-1-yl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid, a glass whose C.I.M.S. contained an MH⁺ peak at m/e 356 and anMNH⁺ peak at m/e 373;

N-[2-endo-hydroxy-3-exo-(3-hydroxyundec-1-yl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxydodec-1-yl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

C. In a similar manner by following the procedure of Example 13.A.1, butsubstituting for2-endo-hydroxy-3-exo-(3-hydroxy-oct-1-yl)bicyclo[3.2.0]heptan-6-one thecorresponding alkyl bicycloheptanone listed in the Preparation 5.C.3.b,the following representative compounds are prepared:

N-[2-endo-hydroxy-3-exo-(3-hydroxy-6-ethyloct-1-yl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclopentylprop-1-yl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid, a glass whose C.I.M.S. contained an MH⁺ peak at m/e 326;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclohexylprop-1-yl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid, a glass whose C.I.M.S. contained an MH⁺ peak at m/e 340 and anMNH⁺ peak at m/e 357;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-phenylprop-1-yl)bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-[2-endo-nydroxy-3-exo-(3-hydroxy-3-(4-chlorophenyl)prop-oct-1-yl)-bicyclo[3.2.0]hept-6-ylidene]aminooxyacetic acid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-(2,4-dimethylphenyl)prop-1-yl)-bicyclo[3.2.0]hept-6-ylidene]-aminooxyacetic acid;

N-[2-endo-hydroxy3-exo-(3-hydroxy-4-phenylbut-1-yl)-bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-(3-trifluoromethylphenyl)prop-1-yl)-bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid;

N-[2-endo-hydroxy-3-exo-(3-hydroxy-4-(4-methoxyphenylbut-1-yl)-bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid.

EXAMPLE 19 Alkynyl, Alkenyl, or Alkyl Aminooxyvaleric Acid of Formula(1) or (2)

This example illustrates methods according to the invention, ofpreparing 5-aminooxyvaleric acid derivatives of alkynyl, alkyl andalkenyl bicycloheptanone isomers (A) and (B). These compounds areprepared following the procedures of Examples 1-3 (A-C) and 7-9 (A-C)and substituting 3-aminooxypropionic acid by 5-aminooxyvaleric acid fromPreparation 7.

EXAMPLE 20 Preparation of Salt Derivatives from Acids

This example illustrates methods for preparing the pharmaceuticallyacceptable salts of the invention. The sodium salt derivative of thecompound of formula (1) prepared in Example 1, for example,N-[3-endo-hydroxy-2-exo-(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid, is prepared by treating a methanolic solution of said acid withone molar equivalent of 1N aqueous sodium hydroxide solution at anambient temperature. Evaporation of the solvents under reduced pressurefurnishes a solid residue of the desired sodium salt.

The sodium salt derivatives of the other compounds prepared in Examples1-18 are prepared similarly using the same procedure.

EXAMPLE 21 Preparation of Acid Derivatives from Salts

This example illustrates methods for preparing acid derivatives fromsalt derivatives of the compounds prepared in Examples 1-18.

The sodium salt ofN-[2-endo-hydroxy-3-exo-(3-hydroxy-oct-1-yl)-bicyclo[3.2.0)hept-6-ylidene]-3-aminooxypropionicacid was dissolved in water or water soluble solvent (as defined above)and acidified with diluted HCl (1N) at 0° to 25° C. to pH 4. The organicmaterial was extracted with suitable solvents, e.g., ethyl acetate,ether, methylene chloride. The organic solution was washed with water,brine dried over magnesium sulfate and evaporated to giveN-[2-endo-hydroxy-3-exo-(3-hydroxy-oct-1-yl)-bicyclo[3.2.0)hept-6-ylidene]-3-aminooxypropionicacid.

Similarly, other salts of aminooxyacids of Examples 1-18 are convertedto their corresponding free acids.

EXAMPLE 22 Preparation of Carboxylic Esters from Acids of Formula (2)

A. Methyl ester ofN-[2-endo-hydroxy-3-exo-(3-hydroxyoct-1-ynyl)-bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid.

A solution ofN-[2-endo-hydroxy-3-exo-(3-hydroxyoct-1-ynyl)-bicyclo[3.2.0]hept-6-ylidene]-aminooxyaceticacid prepared according to Example 16 (0.100 g) in 5 ml of ether istreated with an ethereal solution containing a molar excess ofdiazomethane. The yellow mixture is held at room temperature for 2hours, then acetic acid is added dropwise until the remaining color isdischarged. Solvent is removed by evaporation under reduced pressure,and the virtually pure residue so obtained is given a final purificationby preparative layer chromatography to furnish the title compound.

B. In similar fashion but substituting higher diazoalkanes for thediazomethane employed in the preceeding example, the correspondinghigher alkyl esters of the starting acid are prepared. The requisitediazoalkanes are known. They may be prepared, by conventional methods,e.g. as described in Org. Reactions, 8, 389-94, (1954).

Furthermore, by employing the procedure and diazoalkane reagents of thisExample but substituting the other acid products of formula (2) preparedaccording to Examples 7-12 and 16-18 for the aminooxyacetic acidstarting material utilized above, the corresponding alkyl esters of eachoximinoalkanoic acid product of formula (2) are prepared.

EXAMPLE 23 Preparation of Carboxylic Esters Corresponding to the NovelCarboxylic Acid Products of this Invention of Formula (1)

By reacting the carboxylic acid products of formula (1), obtainedfollowing the procedure of Example 1-6 and 13-15 with diazoalkanesaccording to the method described in the preceeding Example, the alkylesters corresponding to the formula (1) acid starting materials areprepared.

EXAMPLE 24 Preparation of Carboxylic Esters from Acids of Formula (1) or(2) by Reaction of Their Carboxylate Salts with Alkyl Halides

EthylN-[2-endo-hydroxy-3-exo-(3-hydroxyoct-1-ynyl)-bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionate.

The toxicity and explosion hazard engendered by the diazoalkanes makesthem undesirable reagents for large scale esterifications. This Exampledescribes an alternative mild esterification procedure (Bull. Chem. Soc.Japan, 51, 2401 (1978)) more suitable for manufacturing purposes. To asolution ofN-[2-endo-hydroxy-3-exo-(3-hydroxyoct-1-ynyl)bicyclo-[3.2.0]hept-6-ylidene]-aminooxyaceticacid (0.200 g) in benzene (30 ml) are added 4 equiv. of1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), followed by dropwise additionto the stirred DBU-carboxylate complex, of ethyl iodide (1.5 equiv.).After stirring an additional 2 hours at room temperature the reactionmixture is evaporated to 1/3 volume under reduced pressure. Theconcentrate is washed with 3 portions of dilute ice-cold aqueous HCl,twice with saturated brine, dried over Na₂ SO₄, and evaporated to give avirtually pure residue of the desired ethyl ester. By following theabove procedure but substituting other alkyl bromides or alkyl iodidesfor the ethyl iodide used therein, the corresponding alkyl estersderived from the acid starting material of formula (2) are prepared.When the esterifications proceed too slowly at ambient temperature(particularly when alkyl bromides are employed as alkylating agents) itis advantageous to conduct the esterification reaction at the boilingpoint of the reaction system (80° C.).

In similar fashion, by subjecting the acid products (formulas (1) and(2), respectively,) of our invention prepared as described in Examples1-18 to the esterification procedure of the present Example employingthe appropriate alkyl halide as an alkylating reagent, the correspondingesters derived from the free carboxylic acid products of formulas (1)and (2) are prepared.

EXAMPLE 25 Preparation of Free Carboxylic Acid Products, Structures (I)and (II), by Saponification of the Corresponding Esters

This Example describes preparation of the carboxylic acids of ourinvention formula (1) or (2) by saponification of their correspondingalkyl esters. Saponification may be carried out employing a wide varietyof organic and/or inorganic bases under conventional and well-knownreaction conditions. The following procedure is given for illustrativepurposes only and is not intended to be limiting in any sense.

A solution of the methyl ester (0.05 g) of aN-[3-endo-hydroxy-2-exo-(3-hydroxybut-1-yl)-bicyclo[3.2.0]-hept-6-ylidene]-3-aminooxypropionicacid prepared according to procedure of Example 22 or 24 in 3 ml ofmethanol is purged with argon and stirred under an argon atmospherewhile 0.5 ml of in aqueous NaOH is added. Stirring is continued for 4hours at ambient temperature, followed by evaporation of most of thesolvent under reduced pressure. The concentrate is diluted with 10 ml ofH₂ O and, after adjusting the pH to between 5.5 and 6.5, extracted with3 portions of methylene chloride. The combined extracts are washed withsaturated brine, dried over sodium sulfate, and evaporated under reducedpressure to afford the free carboxylic acid of structure correspondingto the carboxylate residue in the ester being hydrolyzed. Similarly, theother esters prepared from the novel oximino acids of our inventionaccording to Examples 22-24 are saponified to furnish the correspondingfree acids of formulas (1) and (2).

EXAMPLE 26

Preparation of Esters from Esters

This example illustrates methods for preparation of other esters fromester compounds prepared in Examples 1-18.

A small piece of sodium was added to a selected alcohol. After all thesolid was digested, an alkoxide solution resulted. Methyl ester ofN-[3-endo-hydroxy-2-exo-(3-hydroxybut-1-yl)-bicyclo[3.2.0]-hept-6-ylidene]-3-aminooxypropionicacid was dissolved in the ethyl alcohol and to this solution was added adrop of the alkoxide solution. After the reaction was complete (asdetermined by TLC), the solution was neutralized and evaporated todryness. The residue was partitioned between ethyl acetate and water.The organic layer was washed with water, brine, and dried over magnesiumsulfate. The solvent was removed under vacuum and the residue was anethyl ester of theN-[3-endo-hydroxy-2-exo-(3-hydroxybut-1-yl)-bicyclo[3.2.0]-hept-6-ylidene]-3-aminooxypropionicacid.

EXAMPLE 27 In Vitro Human Platelet Aggregation Inhibition

Biological activity of the claimed compounds is tested by in vitro humanplatelet aggregation assay. This assay determines the effectiveness ofthe compounds in inhibiting the platelet aggregation

The assay employs modified turbidimetric methods of Born (J. Physiol.,67P (1962) and Evans et al, J. Exp. Med., 128, 877P (1968), and it isbased on the physiological response of the blood platelets to a certainstimuli. In normal circulating blood, platelets are carried alongseparately from each other and they do not adhere to undamagedendothelium. In response to any direct damage to the vascular wall,however, the blood platelets will start to aggregate. Thus, wheneverthere occurs an injury causing bleeding, rupture, cut or another type ofdamage to vascular wall, the collagen fibers in the wall become exposedand platelets immediately start to adhere to them and begin to form aplatelet thrombi. Immediately thereafter, the platelets start to secretelarge quantities of adenosine diphosphate (ADP) which, in turn activatesthe other platelets that adhere to the original platelets and eventuallyform the plug which closes the rupture of the vascular wall. In medicalparlance the first process is called collagen-induced primary plateletaggregation, the second process is called ADP-mediated secondaryplatelet aggregation. This situation can be artificially simulated bynatural platelet aggregation inducers such as collagen, ADP, orarachidonic acid to the human platelet-rich plasma.

Preparation of Human Platelets-Rich Plasma

The blood samples used for the assay are collected into sodium citrateanticoagulant of a final concentration of 0.38%. The platelet-richplasma is collected after centrifugation at 200 rpm at room temperature.To determine whether the platelet-rich plasma needs dilution to obtainoptimal optical density, citrated plasma containing 10⁻⁸ -10⁻⁹ plateletsper milliliter is pipetted into a Spinco transparent plastic centrifugetube. The tube is inserted into a Unicam SP 400 absorptiometer and thelight at the wave-length of 600 mμ is passed through the tube. The darkcurrent is set at infinity and the optical density of distilled water atzero. The plasma is stirred by a magnetic stirrer. If necessary,platelet-rich plasma is diluted with 0.154M sodium chloride to obtainappropriate optical density

Platelet Aggregation Procedure

Platelet-rich plasma of appropriate optical density is mixed withappropriate concentration of tested compounds to make up 1 ml of mixtureof platelet-rich plasma and tested compound. The concentration of eachtested compound varied from 1.0×10⁻⁵ moles to 1.0×10⁻⁹ moles. Eachconcentration is tested individually by number of repetitions varyingfrom 1 to 6. Each sample mixture consisting of platelet-rich plasma andtested compound is incubated for about 3 to 5 minutes under constantstirring at 500 rpm at 30° C. Thereafter, a predetermined optimalconcentration of platelet aggregation inducer is added to each samplemixture. Inducers which are used for testing may be chosen from:

1. Collagen Suspension Inducer

Collagen suspension is prepared by dissolving 2 g of commercial collagen(Sigma Chemical Company) in 100 ml of modified Tyrode's solution at 0°C. and homogenized in the Waring blender for a total of 5 minutes Toremove coarse particle matter the mixture is centrifuged at 810 rpm for10 minutes. The supernatant suspension is then diluted with modifiedTyrode's solution to a concentration which produce maximum aggregationof the platelets being tested, but which, on further dilution, causeless than maximum aggregation.

2. Adenosine Diphosphate Inducer

Adenosine Diphosphate (ADP) is purchased from Sigma Chemical Company.ADP inducer solution of final concentration of 5 μmol is prepared bydissolving 214 mg of ADP in 1 ml of tris buffer (0.01M at pH 9 at 22°C.). Optimal amount of ADP inducer was found to be 5 μmol.

3. Arachidonic Acid Inducer

Arachidonic acid (Nu Chek Prep Co.) inducer solution is prepared bydissolving 150-300 μg of arachidonic acid in 1 ml of a mixture of 10% ofethanol and 90% of 65.6 mmol of sodium carbonate buffer to achieveconcentration 0.5 to 1 mmol.

A tube with the mixture of platelet-rich plasma, tested compound and ADPinducer (5 μmol/10 μl) is inserted into the absorptiometer and opticaldensity changes are recorded on chart. Aggregation of the platelets isdetermined from maximal optical density change. Maximal optical densityof a mixture of platelet-rich plasma with inducer, but without thetested compounds, is taken as 100% of platelet aggregation. The maximaloptical density of the sample mixture of platelet-rich plasma, ADPinducer and appropriate amount of tested compound is compared to themaximal optical density of the sample without tested compound andinhibitory effectiveness of tested compounds is calculated. For eachsample the percentage of the platelet aggregation is calculated and ifmore than one measurement with the same concentration of the testedcompounds are done, the final value is expressed as an average of allmeasurements with ±S.E. The inhibitory concentration is the effectiveconcentration of tested compound which is able to prevent 50% of theplatelet aggregation, where, without the tested compound, the plateletaggregation would have been 100%. PGE₁ has an IC₅₀ of 2-8×10⁻⁸ M.

The compounds of this invention were tested by this procedure and werefound to be active inhibitors of platelet aggregation. (see Table I)

                  TABLE I                                                         ______________________________________                                                               ADP Inducer                                            Compound               IC.sub.50 (M)                                          ______________________________________                                         1.   N--[2-endo-hydroxy-3-exo-(3αS--                                                              1.86 × 10.sup.-8                                   hydroxyoct-1-ynyl)bicyclo-                                                    [3.2.0]hept-6-ylidene]amino-                                                  oxyacetic acid                                                          2.    N--[2-endo-hydroxy-3-exo-(3αS--                                                              8.9 × 10.sup.-8                                    hydroxyoct-1-trans-enyl)-                                                     bicyclo[3.2.0]hept-6-ylidene]-                                                aminooxyacetic acid                                                     3.    N--[2-endo-hydroxy-3-exo-                                                                          1.4 × 10.sup.-6                                    (3αβS--hydroxyoct-1-yl)-                                           bicyclo[3.2.0]hept-6-ylidene]-                                                aminooxyacetic acid                                                     4.    N--[2-endo-hydroxy-3-exo-                                                                          1.25 × 10.sup.-8                                   (3-hydroxy-3-cyclopentylprop-                                                 1-ynyl)bicyclo[3.2.0]hept-6-                                                  ylidene]aminooxyacetic acid                                             5.    N--[2-endo-hydroxy-3-exo-                                                                          1.12 × 10.sup.-8                                   3α-hydroxy-3-cyclopentyl-                                               prop-1-trans-enyl)bicyclo[3.2.0]-                                             hept-6-ylidene]aminooxyacetic                                                 acid                                                                    6.    N--[2-endo-hydroxy-3-exo-                                                                          1.0 × 10.sup.-6                                    (3-hydroxy-3-cyclopentyl-                                                     prop-1-yl)bicyclo[3.2.0]-                                                     hept-6-ylidene]aminooxyacetic                                                 acid                                                                    7.    N--[2-endo-hydroxy-3-exo-                                                                          2.4 × 10.sup.-8                                    (3-hydroxy-3-cyclohexyl-                                                      prop-1-ynyl)bicyclo[3.2.0]-                                                   hept-6-ylidene]aminooxyacetic                                                 acid                                                                    8.    N--[2-endo-hydroxy-3-exo-                                                                          8.8 × 10.sup.-8                                    (3-hydroxy-3-cyclohexyl-                                                      prop-1-yl)bicyclo[3.2.0]-                                                     hept-6-ylidene]aminooxyacetic                                                 acid                                                                    9.    N--[2-endo-hydroxy-3-exo-                                                                          3.2 × 10.sup.-8                                    (3-hydroxydec-1-ynyl)bicyclo-                                                 [3.2.0]hept-6-ylidene]-                                                       aminooxyacetic acid                                                     10.   N--[2-endo-hydroxy-3-exo-                                                                          2.35 × 10.sup.-70                                  (3-hydroxydec-1-yl)bicyclo-                                                   [3.2.0]hept-6-ylidene]-                                                       aminooxyacetic acid                                                     11.   N--[2-endo-hydroxy-3-exo-                                                                          7.0 × 10.sup.-8                                    (3αβS--hydroxyoct-1-ynyl)-                                         bicyclo[3.2.0]hept-6-ylidene]-                                                aminooxyacetic acid                                                     12.   N--[2-endo-hydroxy-3-exo-                                                                          3.1 × 10.sup.-8                                    (3αS--hydroxyoct-1-ynyl)-                                               bicyclo[3.2.0]hept-6-ylidene]-                                                3-aminooxypropionic acid                                                13.   N--[ 2-endo-hydroxy-3-exo-                                                                         6.9 × 10.sup.-9                                    (3αS--hydroxyoct-1-trans-enyl)-                                         bicyclo[3.2.0]hept-6-ylidene]-                                                3-aminooxypropionic acid                                                14.   N--[2-endo-hydroxy-3-exo-                                                                          2.2 × 10.sup.-6                                    (3αβS--hydroxyoct-1-yl)-                                           bicyclo[3.2.0]hept-6-ylidene]-                                                3-aminooxypropionic acid                                                15.   N--[2-endo-hydroxy-3-exo-                                                                          3.1 × 10.sup.-8                                    (3-hydroxy-3-cyclopentylprop-                                                 1-ynyl)bicyclo[3.2.0]hept-6-                                                  ylidene]-3-aminooxypropionic                                                  acid                                                                    16.   N--[ 2-endo-hydroxy-3-exo-                                                                         1.05 × 10.sup.-8                                   (3α-hydroxy-3-cyclopentylprop-                                          1-trans-enyl)bicyclo[3.2.0]hept-6-                                            ylidene]-3-aminooxypropionic                                                  acid                                                                    17.   N--[2-endo-hydroxy-3-exo-                                                                          1.02 × 10.sup.-6                                   (3-hydroxy-3-cyclopentylprop-                                                 1-yl)bicyclo[3.2.0]hept-6-                                                    ylidene]-3-aminooxypropionic                                                  acid                                                                    18.   N--[2-endo-hydroxy-3-exo-                                                                          8.4 ×  10.sup.-9                                   (3-hydroxy-3-cyclohexylprop-                                                  1-ynyl)bicyclo[3.2.0]hept-6-                                                  ylidene]-3-aminooxypropionic                                                  acid                                                                    19.   N--[2-endo-hydroxy-3-exo-                                                                          8.1 × 10.sup.-8                                    (3α-hydroxy-3-cyclohexylprop-                                           1-trans-enyl)bicyclo[3.2.0]hept-6-                                            ylidene]-3-aminooxypropionic                                                  acid                                                                    20.   N--[2-endo-hydroxy-3-exo-                                                                          2.35 × 10.sup.-6                                   (3-hydroxy-3-cyclohexylprop-                                                  1-yl)bicyclo[3.2.0]hept-6-                                                    ylidene]-3-aminooxypropionic                                                  acid                                                                    21.   N--[2-endo-hydroxy-3-exo-                                                                          1.17 × 10.sup.-7                                   (3-hydroxydec-1-                                                              ynyl)bicyclo[3.2.0]hept-6-                                                    ylidene]-3-aminooxypropionic                                                  acid                                                                    22.   N--[ 2-endo-hydroxy-3-exo-                                                                         1.3 × 10.sup.-6                                    (3-hydroxydec-1-                                                              yl)bicyclo[3.2.0]hept-6-                                                      ylidene]-3-aminooxypropionic                                                  acid                                                                    23    N--[2-endo-hydroxy-3-exo-                                                                          1.75 × 10.sup.-7                                   (3-hydroxyoct-1-                                                              ynyl)bicyclo[3.2.0]hept-6-                                                    ylidene] -3-aminooxypropionic                                                 acid                                                                    24.   N--[2-endo-hydroxy-3-exo-                                                                          4.3 × 10.sup.-8                                    (3αβS--hydroxyoct-1-                                               ynyl)bicyclo[3.2.0]hept-6-                                                    ylidene]-3-aminooxypropionic                                                  acid                                                                    25.   N--[2-endo-hydroxy-3-exo-                                                                          4.2 × 10.sup.-7                                    (3αβS--hydroxyoct-1-                                               ynyl)bicyclo[3.2.0]hept-6-                                                    ylidene]-4-aminooxybutyric                                                    acid                                                                    26.   N--[3-endo-hydroxy-2-exo-                                                                          2.1 × 10.sup.-5                                    (3αβS--hydroxyoct-1-                                               ynyl)bicyclo[3.2.0]hept-6-                                                    ylidene]-3-aminooxypropionic                                                  acid                                                                    27.   N--[3-endo-hydroxy-2-exo-                                                                          1.1 × 10.sup.-6                                    (3αβS--hydroxyoct-1-                                               ynyl)bicyclo[3.2.0]hept-6-                                                    ylidene]-4-aminooxybutyric                                                    acid                                                                    ______________________________________                                    

EXAMPLE 27 Acute Toxicity ofN-[2-endo-hydroxy-3-exo-(3-hydroxyoct-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminopropionicacid Materials and Methods

Male Sim: (SW)_(f) BR mice weighing approximately 25 g were randomlyassigned to treatment groups of 6 animals, caged together, and weregiven food and water ad libitum.

The test material was prepared as an aqueous solution or suspension inCMC vehicle (sodium carboxymethyl cellulose, 0.5 g; sodium chloride, 0.9g; benzyl alcohol, 0.9 ml; Tween 80, 0.4 ml; and water to 100 ml). Thetest material and the control vehicle were administered once by theindicated route at a dose level of 10 ml per kg body weight.

Following administration of the test material on day 1, animals wereobserved daily and any deaths were recorded.

    ______________________________________                                        RESULTS                                                                       Test   Dose    Route of     No. of                                                                              No. of                                                                              Days                                  Material                                                                             mg/kg   Administration                                                                             Mice  Deaths                                                                              Observed                              ______________________________________                                        Vehicle                                                                              --      Intraperitoneal                                                                            6     0     14                                    Control                                                                       Test   120     Intraperitoneal                                                                            6     0     14                                    Material                                                                      ______________________________________                                    

Based on the results shown in the above Table,N-[2-endo-hydroxy-3-exo-(3-hydroxyoct-1-ynyl)bicyclo-[3.2.0]hept-6-ylidene]-3-aminopropionicacid, when administered intraperitoneally to mice in a single dose, hasan LD₅₀ of greater than 120 mg/kg. The other compounds of this inventionexhibit similar toxicity.

What is claimed is:
 1. A compound or its optical isomers chosen fromthose represented by the formulas ##STR23## and the pharmaceuticallyacceptable non-toxic salts and esters thereof, wherein:n is an integerfrom one to four; R₁ is hydroxy; R₂ is hydrogen; or R₁ and R₂ togetherare an oxo group; and R₃ is --A--CHOH--R₄ whereinA is --CH₂ --CH₂ --;trans--CH═CH--; or --C.tbd.C--; and R₄ is linear or branched alkyl ofone to twelve carbons, preferably 1-10 carbons, most preferably 3-8carbons, cycloalkyl of three to eight carbons; phenyl optionallysubstituted with one or two identical substituents selected from thegroup consisting of lower alkyl, lower alkoxy, hydroxy, trifluoromethyland halo; or phenylloweralkyl optionally substituted with one or twoidentical substituents selected from the group consisting of loweralkyl, lower alkoxy, hydroxy, trifluoromethyl, and halo.
 2. The compoundof claim 1 and the pharmaceutically acceptable non-toxic salts andesters thereof, wherein the compound is represented by formula (1). 3.The compound of claim 2 and the pharmaceutically acceptable non-toxicsalts and esters thereof, wherein n is 1, 2 or
 3. 4. The compound ofclaim 3 and the pharmaceutically acceptable, non-toxic salts and estersthereof, wherein n is
 1. 5. The compound of claim 4 and thepharmaceutically acceptable non-toxic salts and esters thereof, whereinA is C.tbd.C.
 6. The compound of claim 5 wherein R₁ is OH; R₂ is H; andR₄ is 5 carbon linear alkyl, namelyN-[3-endo-hydroxy-2-exo-(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid and the pharmaceutically acceptable non-toxic salts and estersthereof.
 7. The compound of claim 3 and the pharmaceutically acceptablenon-toxic salts and esters thereof, wherein n is
 2. 8. The compound ofclaim 7 and the pharmaceutically acceptable non-toxic salts and estersthereof, wherein A is C.tbd.C.
 9. The compound of claim 8 wherein R₁ isOH; R₂ is H; and R₄ is 5 carbon linear alkyl, namelyN-[3-endo-hydroxy-2-exo-(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid and the pharmaceutically acceptable non-toxic salts and estersthereof.
 10. The compound of claim 3 and the pharmaceutically acceptablenon-toxic salts and esters thereof, wherein n is
 3. 11. The compound ofclaim 10 and the pharmaceutically acceptable non-toxic salts and estersthereof, wherein A is C.tbd.C.
 12. The compound of claim 11 wherein R₁is OH; R₂ is H; and R₄ is 5 carbon linear alkyl, namely,N-[3-endo-hydroxy-2-exo-(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid and the pharmaceutically acceptable non-toxic salts and estersthereof.
 13. The compound or its optical isomers of claim 1 and thepharmaceutically acceptable non-toxic salts and esters thereof, whereinthe compound is represented by formula (2).
 14. The compound or itsoptical isomers of claim 13 and the pharmaceutically acceptablenon-toxic salts and esters thereof, wherein n is 1, 2 or
 3. 15. Thecompound or its optical isomers of claim 14 and the pharmaceuticallyacceptable non-toxic salts and esters thereof, wherein n is
 1. 16. Thecompound or its optical isomers of claim 15 and the pharmaceuticallyacceptable non-toxic salts and esters thereof, wherein A is C.tbd.C. 17.The compound or its optical isomers of claim 16 wherein R₁ is OH; R₂ isH; and R₄ is 5 carbon linear alkyl, namelyN-[2-endo-hydroxy-3-exo-(3-hydroxyoct-1-ynyl)bicyclo-[3.2.0]hept-6-ylidene]aminooxyaceticacid;N-[2-endo-hydroxy-3-exo-(3αβS-hydroxyoct-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid;N-[2-endo-hydroxy-3-exo-(3αS-hydroxyoct-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid and the pharmaceutically acceptable non-toxic salts and estersthereof.
 18. The compound of claim 16 wherein R₁ is OH; R₂ is H; and R₄is a 7 carbon linear alkyl, namelyN-[2-endo-hydroxy-3-exo-(3-hydroxydec-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid or its optical isomers and the pharmaceutically acceptablenon-toxic salts and esters thereof.
 19. The compound of claim 16 whereinR₁ is OH; R₂ is H; and R₄ is a 5 carbon cyclic alkyl, namelyN-[2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclopentylprop-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid or its optical isomers and the pharmaceutically acceptablenon-toxic salts and esters thereof.
 20. The compound of claim 16 whereinR₁ is OH; R₂ is H; and R₄ is a 6 carbon cyclic alkyl, namelyN-[2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclohexylprop-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid or its optical isomers and the pharmaceutically acceptablenon-toxic salts and esters thereof.
 21. The compound or its opticalisomers of claim 14 and the pharmaceutically acceptable non-toxic saltsand esters thereof, wherein n is
 2. 22. The compound or its opticalisomers of claim 21 and the pharmaceutically acceptable non-toxic saltsand esters thereof, wherein A is C.tbd.C.
 23. The compound or itsoptical isomers of claim 22 wherein R₁ is OH; R₂ is H; and R₄ is 5carbon linear alkyl, namely,N-[2-endo-hydroxy-3-exo(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;N-[2-endo-hydroxy-3-exo-(3αβS-hydroxyoct-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;N-[2-endo-hydroxy-3-exo-(3αS-hydroxyoct-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid and the pharmaceutically acceptable non-toxic salts and estersthereof
 24. The compound of claim 22 wherein R₁ ₁ is OH; R₂ is H; and R₄is a 7 carbon linear alkyl, namelyN-[2-endo-hydroxy-3-exo-(3-hydroxydec-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid or its optical isomers and the pharmaceutically acceptablenon-toxic salts and esters thereof.
 25. The compound of claim 22 whereinR₁ is OH; R₂ is H; and R₄ is a 5 carbon cyclic alkyl, namelyN-[2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclopentylprop-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid or its optical isomers and the pharmaceutically acceptablenon-toxic salts and esters thereof.
 26. The compound of claim 22 whereinR₁ is OH; R₂ is H; and R₄ is a 6 carbon cyclic alkyl, namelyN-[2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclohexylprop-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid or its optical isomers and the pharmaceutically acceptablenon-toxic salts and esters thereof.
 27. The compound or its opticalisomers of claim 14 and the pharmaceutically acceptable non-toxic saltsand esters thereof, wherein n is
 3. 28. The compound or its opticalisomers of claim 27 and the pharmaceutically acceptable non-toxic saltsand esters thereof, wherein A is C.tbd.C.
 29. The compound of claim 28wherein R₁ is OH; R₂ is H; and R₄ is 5 carbon linear alkyl, namely,N-[2-endo-hydroxy-3-exo-(3-hydroxy-oct-1-ynyl)bicyclo[3.2.0]hept-6-ylidene]-4-aminooxybutyricacid or its optical isomers and the pharmaceutically acceptablenon-toxic salts and esters thereof.
 30. The compound or its opticalisomers of claim 15 and the pharmaceutically acceptable non-toxic saltsand esters thereof, wherein A is trans --CH═CH--.
 31. The compound orits optical isomers of claim 30 wherein R₁ is OH; R₂ is H; and R₄ is a 5carbon linear alkyl, namelyN-[2-endo-hydroxy-3-exo-(3-hydroxyoct-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid;N-[2-endo-hydroxy-3-exo-(3αS-hydroxyoct-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid and the pharmaceutically acceptable non-toxic salts and estersthereof.
 32. The compound or its optical isomers of claim 30 wherein R₁is OH; R₂ is H; and R₄ is a 5 carbon cyclic alkyl, namelyN-[2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclopentylprop-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid;N-[2-endo-hydroxy-3-exo-(3α-hydroxy-3-cyclopentylprop-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid and the pharmaceutically acceptable non-toxic salts and estersthereof.
 33. The compound of claim 30 wherein R₁ is OH; R₂ is H; and R₄is a 6 carbon cyclic alkyl, namelyN-[2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclohexylprop1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid or its optical isomers and the pharmaceutically acceptablenon-toxic salts and esters thereof.
 34. The compound or its opticalisomers of claim 21 and the pharmaceutically acceptable non-toxic saltsand esters thereof, wherein A is trans --CH═CH--.
 35. The compound orits optical isomers of claim 34 wherein R₁ is OH; R₂ is H; and R₄ is a 5carbon linear alkyl, namelyN-[2-endo-hydroxy-3-exo-(3-hydroxyoct-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;N-[2-endo-hydroxy-3-exo-(3αS-hydroxyoct-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid and the pharmaceutically acceptable non-toxic salts and estersthereof.
 36. The compound or its optical isomers of claim 34 wherein R₁is OH; R₂ is H; and R₄ is a 5 carbon cyclic alkyl, namelyN-[2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclopentylprop-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;N-[2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclopentylprop-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid and the pharmaceutically acceptable non-toxic salts and estersthereof.
 37. The compound or its optical isomers of claim 34 wherein R₁is OH; R₂ is H; and R₄ is a 6 carbon cyclic alkyl, namelyN-[2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclohexylprop-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;N-[2-endo-hydroxy-3-exo-(3α-hydroxy-3-cyclohexylprop-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid and the pharmaceutically acceptable non-toxic salts and estersthereof.
 38. The compound or its optical isomers of claim 15 and thepharmaceutically acceptable non-toxic salts and esters thereof, whereinA is trans --CH₂ --CH₂ --.
 39. The compound or its optical isomers ofclaim 38 wherein R₁ is OH; R₂ is H; and R₄ is a 5 carbon linear alkyl,namelyN-[2-endo-hydroxy-3-exo-(3-hydroxyoct-1-yl)bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid;N-[2-endo-hydroxy-3-exo-(3αβ8S-hydroxyoct-1-yl)bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid and the pharmaceutically acceptable non-toxic salts and estersthereof.
 40. The compound of claim 38 wherein R₁ is OH; R₂ is H; and R₄is a 5 carbon cyclic alkyl, namelyN-[2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclopentylprop-1-yl)bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid or its optical isomers and the pharmaceutically acceptablenon-toxic salts and esters thereof.
 41. The compound of claim 38 whereinR₁ is OH; R₂ is H; and R₄ is a 6 carbon cyclic alkyl, namelyN-[2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclohexylprop-1-yl)bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid or its optical isomers and the pharmaceutically acceptablenon-toxic salts and esters thereof.
 42. The compound of claim 38 whereinR₁ is OH; R₂ is H; and R₄ is a 7 carbon linear alkyl, namelyN-[2-endo-hydroxy-3-exo-(3-hydroxydec-1-yl)bicyclo[3.2.0]hept-6-ylidene]aminooxyaceticacid or its optical isomers and the pharmaceutically acceptablenon-toxic salts and esters thereof.
 43. The compound or its opticalisomers of claim 21 and the pharmaceutically acceptable non-toxic saltsand esters thereof, wherein A is trans --CH₂ --CH₂ --.
 44. The compoundor its optical isomers of claim 43 wherein R₁ is OH; R₂ is H; and R₄ isa 5 carbon linear alkyl, namelyN-[2-endo-hydroxy-3-exo-(3-hydroxyoct-1-yl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid;N-[2-endo-hydroxy-3-exo-(3αβS-hydroxyoct-1-trans-enyl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid and the pharmaceutically acceptable non-toxic salts and estersthereof.
 45. The compound of claim 43 wherein R₁ is OH; R₂ is H; and R₄is a 5 carbon cyclic alkyl, namelyN-[2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclopentylprop-1-yl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxyaceticacid or its optical isomers and the pharmaceutically acceptablenon-toxic salts and esters thereof.
 46. The compound of claim 43 whereinR₁ is OH; R₂ is H; and R₄ is a 6 carbon cyclic alkyl, namelyN-[2-endo-hydroxy-3-exo-(3-hydroxy-3-cyclohexylprop-1-yl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid or its optical isomers and the pharmaceutically acceptablenon-toxic salts and esters thereof.
 47. The compound of claim 43 whereinR₁ is OH; R₂ is H; and R₄ is a 7 carbon linear alkyl, namelyN-[2-endo-hydroxy-3-exo-(3-hydroxydec-1-yl)bicyclo[3.2.0]hept-6-ylidene]-3-aminooxypropionicacid or its optical isomers and the pharmaceutically acceptablenon-toxic salts and esters thereof.
 48. A pharmaceutical composition forpreventing or treating cardiovascular disorders in mammals whichcomprises an effective dosage of a compound of claim 1 or apharmaceutically acceptable non-toxic salt and ester thereof inadmixture with at least one pharmaceutically acceptable excipient.
 49. Amethod for preventing or treating cardiovascular disorders in mammalswhich method comprises administering to a subject in need of suchtreatment a therapeutically effective amount of a compound of claim 1 ora pharmaceutically acceptable non-toxic salt and ester thereof.